Supramolecular Polymers in Aqueous Media - ACS Publications

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Supramolecular Polymers in Aqueous Media Elisha Krieg,*,†,‡,§ Maartje M. C. Bastings,†,‡,§ Pol Besenius,*,∥ and Boris Rybtchinski*,⊥ †

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, ‡Department of Cancer Biology, Dana-Farber Cancer Institute, and §Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States ∥ Institute of Organic Chemistry, Johannes Gutenberg-Universität Mainz, Mainz 55128, Germany ⊥ Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel ABSTRACT: This review discusses one-dimensional supramolecular polymers that form in aqueous media. First, naturally occurring supramolecular polymers are described, in particular, amyloid fibrils, actin filaments, and microtubules. Their structural, thermodynamic, kinetic, and nanomechanical properties are highlighted, as well as their importance for the advancement of biologically inspired supramolecular polymer materials. Second, five classes of synthetic supramolecular polymers are described: systems based on (1) hydrogen-bond motifs, (2) large π-conjugated surfaces, (3) host− guest interactions, (4) peptides, and (5) DNA. We focus on recent studies that address key challenges in the field, providing mechanistic understanding, rational polymer design, important functionality, robustness, or unusual thermodynamic and kinetic properties.

CONTENTS 1. Introduction 1.1. Supramolecular Polymers 1.2. Importance of Water: Specificity, Robustness, and Role in Biology 1.3. Noncovalent Interactions in Water 1.3.1. Hydrophobic Effect 1.3.2. Hydrophilic Interactions 1.3.3. Coulomb Interactions 1.3.4. H Bonds 1.3.5. van der Waals (VdW) 1.4. Thermodynamic and Kinetic Aspects 1.5. Current Challenges 1.5.1. Mechanistic Understanding and Rational Design 1.5.2. Structural Complexity 1.5.3. Achieving Stability while Preserving Adaptivity 1.5.4. Functional Materials for Real-Life Applications 1.6. Scope of This Review 2. Supramolecular Polymers Found in Nature 2.1. Amyloid Fibrils 2.2. Actin Filaments 2.3. Microtubules 2.4. Supramolecular Biopolymerization Principles as Inspiration for Next-Generation Functional Nanomaterials 3. Synthetic Supramolecular Polymers 3.1. H-Bonding Motifs © 2016 American Chemical Society

3.1.1. Ureido-pyrimidinone (UPy) Motif 3.1.2. Bis-urea Motif 3.1.3. Benzenetricarboxamide (BTA) Motif 3.1.4. Other H-Bond-Driven Polymers 3.2. Large π-Conjugated Surfaces 3.2.1. Perylene Dyes 3.2.2. Rigid Aromatic Rod- and Bent-Shaped Amphiphiles 3.2.3. Other Systems 3.3. Systems Linked by Host−Guest Interactions 3.3.1. Synthetic Host−Guest Systems 3.3.2. Protein-Based Host−Guest Systems 3.4. Small Peptides and Peptide Amphiphiles 3.4.1. Cyclic Peptides and Peptide Conjugates 3.4.2. Aliphatic Peptide Amphiphiles 3.4.3. Aromatic Oligopeptides and Peptide Conjugates 3.4.4. Dendritic Oligopeptide Amphiphiles 3.5. DNA-Based Systems 3.5.1. Simple Hybridization Polymerization 3.5.2. Hybridization Chain Reaction 3.5.3. DNA Tiles and Other Self-Assembled Building Blocks 3.5.4. DNA-Origami Polymers 4. Conclusions and Outlook

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Special Issue: Frontiers in Macromolecular and Supramolecular Science

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Received: June 23, 2015 Published: January 4, 2016 2414

DOI: 10.1021/acs.chemrev.5b00369 Chem. Rev. 2016, 116, 2414−2477

Chemical Reviews Author Information Corresponding Authors Notes Biographies Acknowledgments Glossary References

Review

assembled systems, supramolecular polymers play a key role in the current mechanistic effort to elucidate noncovalent assembly processes. Importantly, it has been realized that supramolecular polymerization can occur under both thermodynamic and kinetic control, with the latter being of primary importance for kinetic mechanistic studies, which have been lacking until recently.29−33,24,34

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1.2. Importance of Water: Specificity, Robustness, and Role in Biology

1. INTRODUCTION

Water is a unique medium for self-assembly.35 Virtually all biological processes take place in aqueous environment. Nature uses water as a critical component for achieving complexity, adaptability, and robustness (cf. section 2).36 Noncovalent interactions in water are distinctly specific and allow unique interaction modes, like those involved in DNA hybridization or protein−ligand complexation. For instance, the selective binding between avidin and its guest biotin has an extremely large thermodynamic driving force (association constant 1015 M−1) and very fast kinetics (association rate constant 7 × 107 M−1 s−1).37 The specific interactions between biological building blocks in water provide a powerful toolbox for noncovalent synthesis and supramolecular polymer design. The possibility to create biocompatible systems is another advantageous property of aqueous supramolecular polymers. For instance, noncovalent polymers based on peptides have shown great potential for various biomedical applications (cf. section 3.4).12,38,39 Hydrophobic interactions can be very strong, thus providing much needed robustness.15 Improved understanding of these interactions is necessary, and it has been recognized that water molecules ought to be treated explicitly in computational studies, rather than regarding them as a continuous dielectric medium.40 Since the strength of the hydrophobic effect often increases with rising temperature, materials that are based on hydrophobic molecules can be extremely heat stable. Importantly, high robustness based on hydrophobic interactions does not necessarily rule out adaptivity.14 For instance, adding an organic cosolvent or introducing electrical charges may drastically weaken the hydrophobic effect, thus enabling reversible construction and destruction of self-assembled systems. Strong noncovalent interactions in water have two important consequences. First, they enable kinetically controlled selfassembly, where pathway-dependent processes may lead to diverse structures based on a single building block. Because of these strong interactions, the kinetics can be sufficiently slow, allowing mechanistic studies, enhanced by an ability to fully map the entire assembly pathway. Second, strong interactions cause structural robustness, which is of primary importance to advance the area of functional supramolecular materials.

1.1. Supramolecular Polymers

The term “supramolecular polymers” invokes immediate analogy to their classical (covalent) counterpartslong onedimensional arrays built from repeating subunits (monomers).1−3 However, unlike classical polymers, supramolecular polymers are linked together by noncovalent interactions; these are usually much weaker than covalent ones, resulting in a prominent contrast: covalent polymers are mechanically and chemically robust, while most supramolecular polymers are not. The lack of robustness has an important consequence: supramolecular polymers are rarely used in applications that require mechanical and chemical stability. However, recent interest in adaptive materials has drawn renewed attention to the field of supramolecular polymers.4−13 Since noncovalent interactions can be reversible and stimuli responsive, materials based on supramolecular polymers are innately adaptive. The critical unsolved question is whether stability can coexist with stimuli responsiveness: in other words, is it possible to create robust yet adaptive materials?14,15 If so, such materials would have major advantages, including easy processing, recyclability, self-healing, stimuli responsiveness, and evolvable properties. Several intriguing examples of functional materials based on supramolecular polymers have been reported in recent years.8,16−21 We focus herein on one-dimensional (1D) supramolecular polymers, which represent the most basic (simplest) type of extended noncovalent systems, being direct counterparts of classical covalent polymers. Such structural analogy has been recently extended to functionality akin to that of covalent polymers. Thus, supramolecular polymers have been employed to create materials that are robust enough to compete with the covalent polymer systems and yet adaptive, representing an entry into a novel class of noncovalent nanomaterials.22,14,15,8 Furthermore, 1D supramolecular polymerization is a test bed for developing design concepts of noncovalent synthesis and elucidating self-assembly mechanisms. The synthetic aspects of noncovalent polymerization are much less developed than those of its covalent counterpart: synthetic methods of covalent chemistry, which were developed over a century, provide a toolbox that is currently unavailable in noncovalent chemistry.23 For example, while the majority of covalent polymerization procedures employ methodologies based on initiation/catalysis, these methods are rarely used in supramolecular polymerization, though recent encouraging developments24−28 may change this trend. Note, however, that the mechanistic framework, which is critical for rational design in covalent chemistry, has only recently started to emerge in noncovalent chemistry. On the positive side, supramolecular polymers are prepared by self-assembly; thus, unlike the covalent systems, they can be both easily constructed as well as destructed, which simplifies their synthesis, recovery, and recycling. Representing a fundamental type of self-

1.3. Noncovalent Interactions in Water

1.3.1. Hydrophobic Effect. The three-dimensional network of hydrogen bonds (H bonds) in water has a profound influence on the noncovalent interactions in an aqueous medium. Hydrophobic interactions represent the most prominent example, resulting from the dominant nature of the H-bonding network that accommodates hydrophobic molecules (Figure 1).41,42,36 The hydrophobic effect has traditionally been considered to be of entropic origin.43 In this picture, the overall number of water H bonds remains more or less intact when hydrophobic solutes are introduced, but in order to accommodate them, water molecules are arranged and 2415


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balances the attractive interactions between hydrophobic moieties. 1.3.3. Coulomb Interactions. Interactions between charged moieties, which are based on Coulomb forces, are very strong and depend on the polarity of the medium. Water, which is a highly polar medium, screens electrostatic interactions, greatly weakening the attraction between charged groups.50,51 The polar water molecules also directly interact with charged groups (specific solvation), further weakening their attraction and imposing repulsion (see above), which leads to dissociation of many salts. In order to enforce attractive Coulomb interactions in an aqueous environment, multivalent interactions between multiply charged species should be involved. Charged groups located in a hydrophobic microenvironment, which protects them from interaction with water, may also exhibit strong interactions. 1.3.4. H Bonds. As with Coulomb interactions, H bonds are drastically weakened in the presence of water. Hence, multivalent or H-bonding motifs protected via hydrophobic shielding are usually involved in aqueous supramolecular polymerization. Although achieving very robust polymers based on H bonds is challenging, the specificity and directionality of these motifs proves immensely valuable for rational polymer design. 1.3.5. van der Waals (VdW). VdW interactions comprise both dipolar and London dispersion interactions that act between uncharged moieties. VdW interactions generally contribute to the binding energies of nonpolar assembly motifs, although in water the strength of the hydrophobic effect normally dominates the polymerization thermodynamics. π−π interactions represent a special case of vdW forces between large π-conjugated surfaces.52 Note that the exact nature of π−π interactions has been debated.53,54,52,55 Electrostatic attraction between electron-rich and electron-poor π-surfaces can play an important role in π-stacking.53,56 Overall, the contribution of π−π interactions to the overall stability of noncovalent assemblies can be substantial.

Figure 1. Hydrogen-bonded network of liquid water around clusters of nonpolar molecules (molecular dynamics simulation). (a) Small hydrophobic molecule imposes geometrical constraints on the Hbonded network but does not necessarily result in breakage of these bonds. (b) Clusters of hydrophobic molecules (or larger hydrophobic groups) result in breakage of H bonds. Oxygen, blue; hydrogen, white; nonpolar molecules, red. Reprinted by permission from ref 40. Copyright 2005 Nature Publishing Group.

lose mobility. The formation of static, “ice-like”, clusters around nonpolar groups was initially invoked, but modern spectroscopy techniques revealed only moderately slower dynamics.36 As the loss of mobility is entropically unfavorable, the hydrophobic solutes tend to aggregate and release the hydration water into the bulk to restore faster dynamics and increase entropy. Indeed, this entropic driving force is a signature of the hydrophobic effect, as observed in numerous thermodynamic studies. The above is true for small hydrophobes, but in the case of large hydrophobic surfaces the picture is entirely different, as the total number of H bonds cannot be maintained.40 Inserting a large nonpolar group into water thus involves breaking of multiple H bonds (Figure 1b). To minimize this enthalpic cost, hydrophobic solutes aggregate, leading to a decrease of interfacial area with the aqueous medium. Therefore, thermodynamic studies show that, in the case of large molecular hydrophobic surfaces, both enthalpic and entropic driving forces play a role, and these have a complex dependence on molecular surface area, shape, and solvent composition.44,45 Although unraveling the factors that influence hydrophobicity is challenging, it is nonetheless clear that large nonpolar surfaces impose strong hydrophobic interactions, which are necessary to create robust aqueous assemblies. The strength of hydrophobic interactions grows approximately linearly with the size of the nonpolar surface.46,47 Moreover, studies on the attraction between macroscopic hydrophobic surfaces in water reveal long-range attractive forces that are much stronger than predicted by existing theories; these forces are yet to be fully understood48 but may be responsible for the fast kinetics of binding between larger hydrophobic surfaces. 1.3.2. Hydrophilic Interactions. Although not a distinct binding mode, hydrophilic interactionsinteractions of water molecules with polar groupsare of primary importance in aqueous supramolecular polymerization. An excellent overview of such interactions is available in the book by Israelachvili.49 Importantly, polar and charged groups provide solubility in aqueous medium. They are strongly solvated, contributing to the steric bulk of the aqueous assemblies. Furthermore, the electrostatic repulsion between equally charged groups counter-

1.4. Thermodynamic and Kinetic Aspects

The thermodynamic and kinetic parameters of supramolecular polymerization are associated with the system’s structure and assembly mechanism. A large number of studies into polymerization thermodynamics have provided a theoretical foundation that is now well established.57−60,3 Isodesmic vs (anti-) cooperative self-assembly are the most basic categories of supramolecular polymerization thermodynamics. They are generally applicable to any solvent environment, and excellent reviews describe these concepts in detail.58,59,3 Importantly, thermodynamic parameters determine a polymer’s robustness, its average length and length-distribution profile, as well as its inclination to disassemble (or assemble) in response to temperature.61,60,45,62 Understanding the relationship between molecular structure and polymerization thermodynamics is therefore key to the rational design of supramolecular polymers with desired properties. Compared to thermodynamics, the kinetics of supramolecular polymerization is often complex and generally less understood. Since supramolecular polymers often reach equilibrium within a short amount of time, the polymerization process usually takes place under thermodynamic control. However, recent studies have shown that supramolecular polymerization can involve exceedingly large kinetic barriers, especially in aqueous medium (Figure 2). Such kinetic effects 2416


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via multiple paths. The solvent plays a critical role in many supramolecular processes, and its influence must be included in any mechanistic model. Furthermore, cooperative and autocatalytic processes (e.g., those leading to nucleation− growth and self-sorting76 behavior) are rather ubiquitous in supramolecular chemistry (especially in aqueous solutions) and contribute to mechanistic complexity. All of these factors make the study of supramolecular polymerization mechanisms difficult. Notably, despite the large number of publications on aqueous supramolecular polymers, few mechanistic studies are available. This lack of understanding impedes rational design of new polymeric systems. Achieving mechanistic understanding and deriving general design rules are therefore key challenges in the field. 1.5.2. Structural Complexity. In its simplest form, a supramolecular polymer can be viewed as a one-dimensional array of identical molecules that has no distinctive structure. Even in this simple unimolecular case, designing a directional binding motif in aqueous media is not trivial, since directional H bonds are weak in water (see above) and hydrophobic interactions lack directionality. In analogy to covalent polymers, which often exhibit welldefined structures (e.g., syndiotactic vs isotactic), noncovalent polymers exhibit a rich variety of different structures, including ribbons, helices, or tubes. Unlike most77,78 covalent polymers, however, supramolecular polymers may undergo reversible rearrangements and transformations between different morphologies. Even in the unimolecular case, supramolecular systems may exhibit higher order self-assembly, leading to complex hierarchical structures.79−81 Such hierarchical selfassembly is particularly prevalent in naturally occurring supramolecular polymers (cf. section 2). One-dimensional supramolecular arrays can also be built from multiple distinct monomers, going beyond the concept of a repetitive unimolecular chain.80 Although allowing for richer structural space, such morphologies are much less understood than the unimolecular ones. Supramolecular copolymers have recently emerged as a new area where advantageous properties result from structural complexity.82 Notable progress has been made in understanding the helicity of some aqueous supramolecular systems and in designing auxiliaries that “lock” certain “molecular chain” morphologies;83 however, controlling the formation of more complex architectures will be key to further development of the field. 1.5.3. Achieving Stability while Preserving Adaptivity. Despite the general weakness of noncovalent bonds, strategies toward robust supramolecular polymers have been developed. For instance, multivalent interactions are sufficiently strong to provide a viable platform for functional materials.84,35 With respect to stability, water is an advantageous solvent, since it enables strong noncovalent (i.e., hydrophobic) bonds. Attenuation of hydrophobic interactions can be achieved by a variety of methods, e.g., by addition of an organic cosolvent. Notably, mechanically strong yet adaptive polymeric systemssuch as actin filaments, which assemble and disassemble according to functional needsare prominent in living matter; thus, bioinspired synthetic systems that continuously undergo construction−destruction cycles can be envisaged. Overall, the design of strong noncovalent bonds that are reversible (upon applying specific external stimuli)85 is of great importance. 1.5.4. Functional Materials for Real-Life Applications. Despite the rapidly growing interest in supramolecular

Figure 2. Schematic energy diagram of supramolecular polymerization involving large kinetic barriers. Kinetically controlled supramolecular polymerization enables pathway-dependent polymer growth and isolation of different metastable morphologies, assembled from the same molecular building block. Reprinted with permission from ref 30. Copyright 2011 John Wiley and Sons.

were first observed in self-assembling block copolymer63,64 but have now been also realized in supramolecular polymerization of small molecules.30,65,34,66 As a result of large kinetic barriers, hysteresis effects, coexistence of multiple metastable products, and pathway-dependent self-assembly are observed (Figure 2). Importantly, slow assembly kinetics provide control over supramolecular polymerization, for instance, via seeded growth of polymer fibers from a solution of metastable monomers. Specific examples of supramolecular polymerization taking place under thermodynamic versus kinetic control can be found in sections 2 and 3. For quantitatively studied systems we will discuss selected thermodynamic and kinetic parameters, in particular, association constants (Ka), as well as rate constants of polymer growth (k+) and shrinkage (k−), based on the standard definitions of these parameters.58,29,3 1.5. Current Challenges

1.5.1. Mechanistic Understanding and Rational Design. While the distinct mechanisms of breakage and formation of covalent bonds have been extensively studied, a mechanistic framework of noncovalent chemistry is only starting to transpire.23 Defining a set of standardized characterization methods for supramolecular polymers would be desirable, in order to allow direct comparison of different systems, and leading to better understanding and rational design.67 Computational studies on supramolecular polymerization in water are challenging, due to the systems’ size, complexity, and dominant role of the solvent water. Hence, detailed computational investigations of aqueous supramolecular polymers have only recently emerged.68−72,20,73 To date, most computational work has focused on peptidic systems using (coarse-grained) molecular dynamics (MD) or Monte Carlo (MC) simulations.74,75 These studies provided insights into conformational fluctuations, nucleation, growth, and higher order aggregation processes. As computational methods become more powerful, they are expected to play an important role in advancing noncovalent polymer synthesis. Noncovalent bonding either is reversible, leading to equilibrating systems, or, if kinetically controlled, may proceed 2417


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Figure 3. Example of the secondary structure in an amyloid fibril. In the cross-β conformation the polypeptide chains (i.e., the β-strands) are oriented perpendicular to the direction of fiber propagation. Multiple H bonds (red) facilitate the supramolecular polymerization into extended βsheets and provide structural stability.123 This example shows parallel β-sheets, but also antiparallel conformations exist.124

borderline case: a transition from 1D fibers to 3D networks, giving rise to solid-like material properties. Hydrogels have surpassing importance in materials applications, and we therefore highlight selected examples. Second, synthetic coordination polymers, which embody a large group within supramolecular polymers, are not discussed (with exception of metal guest/protein host systems). Whereas coordination polymers show great potential for achieving high stability, their properties are dominated by the covalent nature of dative bonds. The reader is referred to the existing reviews of this field.92−99 Third, only polymers based on well-def ined molecular building blocks are discussed herein. This excludes selfassembling block copolymers or linear arrays of most types of colloid particles.100 Fourth, the massive number of simple surfactant molecules forming worm-like micelles101−103 is beyond the scope of this review. Last, we exclude any type of mechanically interlocked systems, such as polycatenanes.104 Although these systems can be regarded as supramolecular polymers, their strength and irreversible formation reflects the covalent foundation to their mechanical bonds.

polymers, the area of organic functional materials is currently dominated by covalent polymers. Although still exotic, supramolecular polymers are entering the arena of commercial applications.86 While supramolecular polymers may not surpass the mechanical strength of covalent polymer, increasing numbers of studies report on functional supramolecular polymers, which may eventually prove transformative for the areas of materials science and nanotechnology.8 For instance, aqueous supramolecular polymers have found various applications in biomedical engineering.12 Yet, a key question remains open: will supramolecular polymers rival and even outperform their covalent counterparts beyond niche applications? 1.6. Scope of This Review

This review focuses on linear (i.e., one-dimensional) supramolecular polymers that assemble in water, aqueous solutions containing salts, or solvent mixtures containing water as the main component. We will first describe naturally occurring supramolecular polymers; these systems have enormous importance and rich functionality. In particular, we will discuss three well-studied types: amyloid fibrils (section 2.1), actin filaments (section 2.2), and microtubules (section 2.3). We will highlight their structural, thermodynamic, kinetic, and nanomechanical properties as well as their importance for the advancement of bioinspired supramolecular polymer materials. We will then turn to synthetic supramolecular polymers, specifically focusing on recently reported polymers that address key challenges in the field: systems that provide mechanistic understanding and rational design, give rise to interesting kinetic or thermodynamic properties, have high robustness and adaptive properties, or provide new functionality and potential real-life applicability. These polymers will be divided into five classes: Systems based on H-bond motifs (section 3.1), large πconjugated surfaces (section 3.2), host−guest interactions (section 3.3), peptides and peptide amphiphiles (section 3.4), and systems based on DNA (section 3.5). Several important types of polymeric systems are beyond the scope of this review. First, the restriction to linear polymers excludes 2D and 3D arrays, such as those found on surfaces, in molecular crystals, or in branched micellar networks,87−91 which require separate thermodynamic, kinetic, and mechanistic models. The entangled self-assembled nanofibers commonly found in supramolecular hydrogels are an intriguing

2. SUPRAMOLECULAR POLYMERS FOUND IN NATURE Nature makes extensive use of polymeric materials: the most prominent examples are polynucleotides (DNA and RNA), polysaccharides (e.g., cellulose), and polypeptides. In these biopolymers the monomer units are linked together by covalent bonds. The stability of covalent bonds is crucial for central biological functions, such as storage and transport of genetic information (performed by DNA and RNA), or for complex biochemical or biophysical tasks (performed by proteins) that require precise geometric arrangement of different groups. In contrast, a naturally occurring noncovalent supramolecular polymer with a programmable sequence (analogous to DNA, RNA, or proteins) has not yet been reportedpossibly because reversible association and dissociation of monomer molecules at the chain ends, as well as chain rupture, could thwart the conservation of a sequence-defined noncovalent polymer chain. Nonetheless, supramolecular polymers are found in large quantities in living systemsexamples of these include cytoskeletal filaments (F-actin, microtubules, intermediate filaments),105,106 amyloid fibrils,107 collagen,108 flagellar fila2418


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ments of bacteria,109 and polymers of viral proteins.110,111 These supramolecular polymers are vital for key biological functions, such as cell division and migration, serving as templates and structural modules, mediators and components for actuation and propulsion, as well as for regulation of various physiological processes.112,113 Recent progress in structural determination, especially with use of cryo-electron microscopy (cryo-EM), has advanced our understanding of the intermolecular forces and mechanisms involved in the formation of supramolecular biopolymers.114,115 Herein, we focus on three important types of supramolecular biopolymers: (1) Amyloid f ibrils, supramolecular ribbons present in very diverse biological contexts, (2) actin f ilaments, supramolecular fibers that are important components of the cytoskeleton and the contractile apparatus of muscle cells, and (3) microtubules, which represent another component of the cytoskeleton and are particularly important for the structure and function of neurons. We focus on the description of their supramolecular architecture, the role of noncovalent binding interactions, assembly mechanisms, polymerization thermodynamics and kinetics, as well as nanomechanical properties and potential applications.

Figure 4. Amyloid fibrils formed by an 11-residue peptide.114 (a) Hierarchical architecture, comprising secondary, tertiary, and quaternary structural elements. (b) AFM image, showing helical supramolecular nanofibers with high aspect ratio and relatively uniform diameter. (c) Atomic structure of one polymorph of the supramolecular polymer. Adapted with permission from ref 114. Copyright 2013 National Academy of Sciences.

2.1. Amyloid Fibrils

Amyloids represent a class of biological supramolecular polymers, which appears to be ubiquitous in Nature116 and shows promising potential for the area of artificial functional biomaterials.117,118 Most prominently, formation of amyloid fibrils is associated with protein misfolding in various neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, Huntington’s, and Creutzfeldt−Jakob disease. However, recent studies revealed that amyloid fibrils also fulfill useful functions in various biological systems, including in bacteria, fungi, and even mammals,112,119−121 leading to the emerging notion that amyloids in fact represent a universal form of proteinaceous materials that are alternative to discrete protein monomers and complexes.116,118,107 Amyloid fibrils are structurally defined as fibrillar aggregates of polypeptide chains with a cross-β conformation,122 in which polypeptide chains are oriented perpendicular to the direction of fiber propagation (Figure 3). The polypeptides primarily interact via multiple H bonds between the backbone amide groups of adjacent polypeptide chains, facilitating the formation of extended β-sheets and resulting in supramolecular polymerization. Interestingly, the ability to form amyloid fibrils under certain conditions seems to be a generic feature of polypeptide chains and does not necessarily require a specific sequence.116 Amyloids exhibit a complex higher order hierarchical architecture that involves pairwise packing of β-sheets and further aggregation, which in turn creates unbranched and twisted ribbons with high aspect ratios.116 The atomic structure of an 11-residue fragment of the protein transthyretin was recently studied in detail (Figure 4);114 it revealed pairs of tightly packed β-sheets (protofilaments) that are self-assembled into filaments, and multiple filaments comprise the fibril. Polymorphs consisting of differing numbers of filaments were found to coexist.114 Typical lengths of amyloid fibrils are in the order of several micrometers, and widths are around 100−200 Å, with 5−12 Å spacings between the tightly packed β-sheets and 4.6−4.8 Å spacings between neighboring peptide chains within the βsheets.114,122 The intermolecular binding within amyloid fibrils involves a number of different interactions, including H bonds

(mostly within but also between β-sheets), vdW interactions, dipole−dipole interactions (e.g., between the C- and N-termini of the polypeptide chains) and π−π interactions (between aromatic residues), as well as hydrophobic effects.114,123,125 Notably, some silk proteins assemble in vitro into nanofibers that exhibit a structure remarkably similar to amyloid fibrils:126 The proteins in these fibers adopt a cross-β conformation, though with significantly tighter packing of the β-sheets. However, natural silk fibers have a complex structure where the β-sheets are embedded in amorphous and crystalline domains, along with random coils and helical structures.127,128 Amyloid fibrils assemble from polypeptides via a nucleation− growth mechanism.129,130 It is believed that in the nucleation stage micelle-like structures (prefibrillar aggregates) are transiently formed via nonspecific oligomerization;116 subsequently, in the elongation regime, fibril growth occurs by addition of soluble proteins to the fibril ends. Amyloids can assemble under reversible equilibrium conditions.130 In particular, the polypeptide Aβ(1−40) assembles with an elongation Gibbs free energy of −38 kJ/mol in phosphatebuffered saline (PBS) at 37 °C.131 However, within an experimentally accessible temperature and concentration range, amyloid formation is most often irreversible,130 which complicates the elucidation of polymerization thermodynamics and suggests the existence of high kinetic barriers and/or large thermodynamic driving forces. In fact, some amyloids exhibit remarkable stability and conservation of morphology over a wide range of pH, temperature, ionic strength, and mechanical stress and display inertness toward proteolysis and dehydration.117 The complete formation of long amyloid fibrils can be very rapid132 or can take up to several days or weeks, depending on the polypeptide sequence and incubation conditions.133−135 Amyloid fibrils also have excellent mechanical properties.136 Their Young’s moduli are in the range of 0.2−20 GPa, matching those of silks, and their strengths in the range of 0.1− 0.8 GPa exceed those of most other proteinaceous materials 2419


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(with the exception of silk).136 This high strength and stiffness, relative to those for other biological materials, is likely due to the high density of multiple H bonds that run in the direction of the fiber propagation.123 The properties of the amino acid side chains in the polypeptide molecules strongly influence the bending rigidity of the amyloid fibrils and yield fibrils with very different persistence lengths.123 Due to their robustness, excellent mechanical properties, and potential biocompatibility, interest in the rational design of functional amyloids and for applying these as materials in bionanotechnology is rapidly growing.117,118,137,138,133 Examples include the application of amyloids as stimuli-responsive gels,139,140 templates for the construction of metal and semiconductor nanostructures141,142 and high-density linear arrays of metalloporphyrins134 for drug delivery,135 tissue engineering,143 catalysis,144 sensing,145 retroviral gene transfer,132,133 and carbon dioxide capture.133,146

bonds in the actin polymer115 and confirming the earlier suggestion that hydrophobic interactions are central to the binding between the actin monomers.149 Like a lock-and-key interaction, the hydrophobic region of actin’s flexible D-loop inserts into a hydrophobic groove on the adjacent monomer, thereby linking the polymer chain together. Interestingly, some regulating proteins may achieve controlled disassembly of actin filaments by the weakening of these hydrophobic interactions via redox chemistry.115,152 Besides contacts between hydrophobic groups, multiple intra- and interstrand salt bridges stabilize the filament. Overall, the linear array of proteins in each strand is firmly held together by multiple noncovalent bonds, whereas the two strands are attached to each other by fewer interstrand contacts.115 Actin filaments assemble via a nucleation−elongation mechanism,57 and the nucleus is believed to be a trimer.154 Such cooperative polymerization is a common feature in biological supramolecular polymers. Cooperativity enables biological systems to control the polymerization process and to help suppress undesired spontaneous and random growth of new polymer chains. The thermodynamics and kinetics of polymerization depend on the adenine nucleotide that is bound to the protein (ATP-actin vs ADP-actin). Chain elongation of ATP-actin is more favorable than that of ADP-actin, but in both cases it has a relatively moderate driving force (Ka in the order of 106−107 M−1 for ATP-actin and ∼5 × 105 M−1 for ADPactin). Rapid kinetics govern monomer association to and dissociation from actin filaments.155,156 The association of ATP-actin to the barbed end of the filament is essentially diffusion limited (k+ = 1.2 × 107 M−1 s−1), whereas the rate constant is somewhat smaller for ADP-actin (k+ = 3.8 × 106 M−1 s−1).156,113 In contrast, the rate constants for monomer association and dissociation are 1 order of magnitude lower at the pointed end of the filament. Importantly, filamentous actin has an enzymatic activity for ATP hydrolysis, and thus, once it is polymerized, ATP-actin is slowly converted to ADP-actin, with a corresponding change in its polymerization kinetics and thermodynamics. The continuous conversion of ATP-actin to ADP-actin along with its polarity-dependent polymerization kinetics give rise to an intriguing phenomenon, called treadmilling: in a certain concentration regime, the polymer chain grows on one end while simultaneously shrinking at the other.157 The basic mechanism of treadmilling is illustrated in Figure 6: the rapidly exchanging barbed end remains rich in ATP-actin, while the slower exchanging pointed end becomes enriched in ADPactin. If the amount of ADP-actin in solution is below its critical concentration for chain elongation, the pointed end gradually depolymerizes, as the barbed end continues to grow. When growth and shrinkage at the two ends of the polymer occurs at the same rate, the filament maintains a constant length while consuming energy in the form of ATP. In the cell, the released ADP-actin is converted back to ATP-actin, thereby replenishing the source of activated monomers that sustain the treadmilling process. As a result of treadmilling, apparent migration of actin filaments on a surface can be observed under the fluorescence microscope.158 The process of treadmilling may appear to be a waste of energy for the cell; however, dynamic behavior that takes place far from thermodynamic equilibrium is ubiquitous in Nature and serves many purposes, including the attenuation of external perturbations such as temperature fluctuations.159 Moreover, biological cells control treadmilling via regulatory

2.2. Actin Filaments

Actin, a 42 kDa globular monomer (G-actin), is one of the most abundant proteins in eukaryotic cells. It contains an adenine nucleotide (adenosine triphosphate (ATP) or adenosine diphosphate, (ADP)), which is important for regulation of its polymerization (see below). G-actin selfassembles into microfilaments (F-actin) that are central components of the cytoskeleton and in the contractile apparatus of muscle cells. F-actin provides structural stability to the cell and participates in transport processes.113,147 The growth of actin filaments can generate physical force, which is used to control the shape of cells and to facilitate cellular motility. In the cell, various other proteins bind to actin and thereby regulate its controlled nucleation, polymerization, depolymerization, bundling, and cross-linking.148 Herein, we focus on the description of pure actin polymers, leaving aside the influence of accessory biomacromolecular agents in biological systems.148 The actin filament is a helical ribbon that comprises two parallel strands, each of which is a linear array of the protein monomer (Figure 5).149,150 The ribbon has a width of ∼8 nm, a thickness of ∼5 nm, and a helical repeat of 36 nm, with all actin monomers oriented along the filament axis. The filament is therefore structurally polarized, with a barbed (plus) end and a pointed (minus) end.151 Recently, a high-resolution structure was reported, revealing the atomic details and intermolecular

Figure 5. Structure of actin filaments. (a) TEM of negatively stained filaments. Reprinted with permission from ref 115. Copyright 2014 Nature Publishing Group. Scale bar: 50 nm. (b) Molecular model of the actin filament structure (PDB 3B63).153 The filament consists of two helical strands (red and blue), each composed of a linear array of proteins that have uniform orientation along the fiber axis. 2420


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potential applications have been suggested. The biological functions of actin filaments have been extensively studied and can now be reproduced in vitro via the use of the large toolbox of the biological machinery. For instance, actin-binding motor proteins (e.g., myosin) can perform actuation; reversible (de)polymerization of the filaments can be triggered in response to ATP or by regulating proteins such as profilin and cofilin. Willner and co-workers used stepwise self-assembly of actin filaments, decorated with gold nanoparticles, to template the growth of conductive gold nanowires.166 When deposited on a surface that was decorated with myosin motor proteins, these nanowires could be moved on demand via the addition of ATP, suggesting their potential use as nanoswitches. Other groups have prepared similar structures, based on actin/ semiconductor hybrid systems.167 Related actin/myosin nanomechanical devices were also used to direct the transport of single cells168 and for controlled unidirectional movement of actin filaments along silicon nanowires.169 Actin filaments have additionally been used as structural components in vesicles.170 Such actin-reinforced vesicles have a tunable shape and increased mechanical stability and may therefore have practical applications as drug delivery vehicles.

Figure 6. Treadmilling: self-organization of actin filaments. The plus end of the actin filament (left side) is rich in ATP-actin (T, red), whereas the minus end is rich in ADP-actin (D, green). The equilibrium for ATP-actin polymerization at the plus end is shifted toward the aggregated state and results in polymer growth. The equilibrium of ADP polymerization at the minus end is shifted toward the monomer, leading to spontaneous depolymerization. While the polymer length and composition may remain constant, there is a continuous flux of monomers through the fiber. Released ADP-actin monomers are converted back to ATP-actin in the cell, thus replenishing the source of activated monomers.

2.3. Microtubules

Microtubules (MTs) are supramolecular tubes formed by polymerization of the protein tubulin. MTs have several structural and functional similarities to actin filaments. Tubulin is found in large amounts in eukaryotic cells, especially in neurons.171,172 MTs are important components of the cytoskeleton, regulating cell shape, movement, cell division, and transport processes.171 In particular, transport is achieved by the microtubule-binding motor proteins kinesin and dynein, which use MTs as tracks to facilitate directional movement. MTs have a hierarchical structure: the basic building block is a heterodimer comprising α- and β-tubulin, both of which have almost identical tertiary structures. The dimers assemble headto-tail into a linear array of alternating α- and β-subunits,173 called a protof ilament. A variable number of protofilaments (usually around 13) are bundled together into a hollow cylinder. MTs have an outer diameter of about 30 nm and are several micrometers in length (Figure 7);174,171 their wide tubular structure leads to a bending rigidity that is significantly higher than that of actin filaments (persistence length ≈ 5200 μm for microtubules vs ∼18 μm for actin filaments),162 and the reported Young’s moduli for MTs range from 12 MPa to 1 GPa.162,175,176 As with actin filaments, MTs have a plus end and a minus end, with β-subunits pointing toward the plus end (Figure 7d). This structural polarity is critical for the intracellular function of MTs, for instance, in determining the

proteins and utilize it for the generation of force that is vital for transport and cell motility.160 Actin filaments have a Young’s modulus in the order of 0.1− 2 GPa, comparable to that of various amyloid fibrils (Table 1).136,161 However, as a consequence of weaker supramolecular bonding, actin filaments have significantly lower tensile strength and are slightly more flexible than fully assembled amyloid fibrils of similar dimensions.123,162 We highlight two ways in which polymerization of actin is fundamentally different from that of amyloids. (1) Due to fast kinetics and moderate thermodynamic driving force, actin filaments are highly dynamic structures that can be rapidly assembled and disassembled on demand. (2) While amyloid fibril formation is a process toward thermodynamic equilibrium,107 actin’s self-organization157,163 (treadmilling) requires an energy source (provided in form of ATP). Therefore, actin filaments illustrate the fascinating potential of self-organized (i.e., dynamic and off-equilibrium) supramolecular polymers, which are very rare in the realm of synthetic systems.164,165 Although practical utilization of actin filaments is less developed than that of amyloid fibrils, a growing number of

Table 1. Comparison of Measured Thermodynamic, Kinetic, and Mechanical Parameters of Naturally Occurring Supramolecular Polymers association constant for chain elongation, Ka [M−1] nucleus size association rate constant,a k+ [M−1 s−1] dissociation rate constant,a k− [s−1] Young’s modulus [GPa] bending rigidity [N m2] persistence length [μm] tensile strength [GPa] a

amyloid fibrils

actin filaments

microtubules

ref

0.1−20 10−26−10−24 0.5−100 0.1−0.8

5 × 105−107 3 1.2 × 107 1.4 0.1−2 7 × 10−27−7 × 10−26 4−18 ∼0.01

∼105 7−15 5.8 × 107 concentration dependent 0.01−1 10−24−2 × 10−23 ∼5200

156,179,183 154,180−182 156,184 184 136,162,175,176 123,162,176 136,162,204 136

Estimated values for the association/dissociation of nucleotide triphosphate-containing monomers to the plus end of the polymer. 2421


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Figure 7. Structures of microtubules (MTs) during elongation and shrinkage. (a) Cryo-TEM of growing MTs. The polymer grows from its ends by addition of single α/β-tubulin heterodimers. At this stage, the MTs have clear-cut end caps (marked by black arrows). (b) Cryo-TEM of MTs during polymer shrinkage. End caps are frayed, and free protofilament fragments are observed in solution, indicating that depolymerization occurs via dissociation of oligomers (marked by black arrows). (c) Schematic depiction of microtubule depolymerization. (a−c) Adapted with permission from ref 174. Copyright 1991 Mandelkow et al. (d) High-resolution cryo-EM structures of the tubulin heterodimer in the microtubule. Hydrolysis of GTP (bound to the ß-tubulin monomer) destabilizes longitudinal interactions along the protofilament. Adapted with permission from ref 185. Copyright 2014 Cell Press.

significantly stronger binding than their GDP-containing analogs.171,183 Overall, tubulin polymerization is governed by rapid kinetics, which are diffusion limited at the plus end (k+ = 5.8 × 107 M−1 s−1).184 Interestingly, MT polymerization and depolymerization do not follow identical pathways (Figure 7a−c): polymer growth takes place by addition of heterodimers to the polymer ends, whereas depolymerization involves fraying of the polymer ends and dissociation of bent protofilament fragments (Figure 7b and 7c).174 The reason for this irreversible assembly/ disassembly pathway lies in the hydrolysis of the β-subunit’s guanine nucleotide: the continuous conversion of GTP to GDP within the MT induces structural changes that alter the preferred curvature of the protofilaments,186 thus destabilizing the MT. During growth, the polymer ends retain a high GTP content, as they steadily bind new dimers. Stabilized by the GTP-rich end caps, the protofilaments in the GDP-rich body of the MT therefore remain in a mechanically stressed, metastable state.171 At lower dimer concentrations, however, the polymer grows too slowly to retain its GTP-rich end caps; as a result, the protofilaments relax into a bent state, separate from each other, andowing to the loss of lateral interactionsare prone to fully dissociate from the MT. The described polymerization mechanisms demonstrate that MTsmuch like actin filamentsare self-organized supramolecular polymers. In fact, MTs also undergo treadmilling under certain conditions.187 Moreover, MTs exhibit an interesting phenomenon called dynamic instability:188 at

direction of the movement of motor proteins along the polymer. Longitudinal binding between tubulin heterodimers within the protofilament chain is largely driven by hydrophobic and polar interactions between their two extensive (∼3000 Å2), shape-complementary interfaces.177 Intradimer binding is further stabilized by a salt bridge.177 These noncovalent interactions result in a large thermodynamic driving force for dimerization, with an association constant in the order of ∼1011 M−1 for heterodimer formation178 but only ∼105 M−1 for association of heterodimers with the end of the MT.179 Adjacent protofilaments are largely held together by electrostatic interactions. Notably, a guanine nucleotide (guanosine triphosphate (GTP) or guanosine diphosphate (GDP)) is present at the center of each subunit’s interface. Analogous to ATP and ADP in actin filaments, GTP and GDP participate in intermolecular binding and modulate MT polymerization kinetics and thermodynamics (see below). Tubulin polymerization is a complex, extremely dynamic, and strongly cooperative process.171 Self-nucleation in vitro is poorly understood, though various nucleation models have been proposed, which suggest nucleus sizes in the range of 7− 15 heterodimers.180−182 Within the cell, nucleation is controlled by diverse factors, such as the state of the bound nucleotide, presence of MT-binding proteins, and covalent modifications of the tubulin monomers.171 As with actin filaments, the self-assembly dynamics of MTs is significantly faster at the plus end, and GTP-containing dimers exhibit 2422


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intermediate concentrations (e.g., ∼15 μM) individual MT ends frequently alternate between long periods of steady growth and shorter periods of rapid, “catastrophic” depolymerization (Figure 8).189 Hence, the self-organization of MTs can

(e.g., temperature changes), which could otherwise alter various polymer properties.159 Dynamic off-equilibrium polymerization also enables rapid construction or destruction of polymer fibrils, as needed. (3) Regulation: In vivo, supramolecular polymerization is regulated via numerous biomolecules, which serve as the cell’s toolbox to inhibit, stimulate, or nucleate polymer growth. (4) Polarization: Unlike many synthetic supramolecular polymers, most naturally occurring supramolecular polymers are structurally polarized. Two ends of the polymer fibers are thus distinguishable to the organism and may differ in their kinetic and thermodynamic properties. Such structural polarization is essential for various functions, such as directional transport of molecular cargo via motor proteins. The thermodynamic, kinetic, and nanomechanical properties of naturally occurring supramolecular polymers (Table 1) evolved to suit demanding biological tasks. The sophistication of supramolecular polymerization that occurs in Nature is yet unparalleled in the realm of synthetic polymers (cf. section 3). Numerous synthetic systems contain biomolecular building blocks (e.g., peptide chains, proteins, biological macrocycles, and DNA) and utilize the intermolecular binding motifs in their supramolecular polymerization (cf. sections 3.3−3.5). Combining the intriguing features of supramolecular biopolymers with the vast design space of synthetic compounds should lead to the next generation of self-organizing, self-healing, (multi)stimuli-responsive, and “informed”201 functional noncovalent materials.202,203

Figure 8. Dynamic instability of microtubules (MTs). The change of MT length at the plus (top) and minus end (bottom), as observed in dark-field microscopy. Both ends alternate between long periods of steady growth and short periods of “catastrophic” depolymerization. Adapted with permission from ref 189. Copyright 1986 Nature Publishing Group.

facilitate unusually rapid, “spring-loaded” transitions at constant temperature and concentration. Within the cell, the selforganization of MTs is controlled by various MT-binding proteins, which is crucial for multiple functions.190,191 As with actin filaments, MTs can be readily grown in vitro, making them accessible for various applications related to functional materials and nanodevices.192,193 Some of these applications involve kinesin or dynein motor proteins, which bind to the MT and facilitate controlled actuation. For instance, a single kinesin molecule is sufficient to perform unidirectional movement of a MT on a surface;194 this actuation is fueled by the hydrolysis of ATP. More recently, systems based on MTs and motor proteins have been used for controlled and directed nanoscopic transport of colloid cargo,195,196 to template the growth of temperature-responsive polymer brushes,197 and for the formation of extended one-dimensional arrays of MT segments.198 Notably, spontaneous depolymerization of MTs can be suppressed by chemically cross-linking their heterodimer building blocks,199 which then protects the MTs from disassembling while preserving various other functional properties.

3. SYNTHETIC SUPRAMOLECULAR POLYMERS There is growing interest in the field of functional supramolecular polymers.8 Synthetic supramolecular polymers have been subdivided according to varying criteria, such as the physical nature of the intermolecular interactions, the type of monomer building block, or the thermodynamics of polymerization.3 Here, we describe five categories of polymers that are loosely classified by the primary binding motif that governs their formation: (1) H-bonding motifs, (2) π−π and hydrophobic interactions, (3) host−guest complexes, (4) peptides and peptide amphiphiles, and (5) systems based on DNA. There is significant overlap between these categories, and many supramolecular polymers in fact employ combinations of binding motifs that work in concert with (or orthogonal to)10,99 each other. For instance, DNA hybridization is governed by H bonding but also has significant contributions from π−π and hydrophobic interactions.205 While many biological systems excel at controlling supramolecular polymerization (cf. section 2), synthetic chemistry provides access to a vast space of functional groups that are not found in nature. Synthetic supramolecular polymers are therefore able to combine the best of two worlds: bioinspired functionality from natural systems with the accessibility and tunable features of synthetic compounds. As a result, synthetic molecules enable fabrication of robust supramolecular materials with promising applications. Besides their functionality, synthetic polymers are being studied at a more fundamental level, for example, to gain insights into noncovalent polymerization mechanisms, thermodynamics, and kinetics.

2.4. Supramolecular Biopolymerization Principles as Inspiration for Next-Generation Functional Nanomaterials

Overall, several remarkable properties are ubiquitously found in supramolecular biopolymers: (1) Cooperativity: Cooperative effects govern the assembly of most supramolecular biopolymers.57,111,109,200,171 Involving cooperative (nucleation/elongation) mechanisms enables biological systems to control polymer length and to suppress undesired spontaneous polymerization. (2) Self-organization: Dynamic off-equilibrium processes, such as treadmilling and dynamic instability, dominate biological supramolecular polymers. These processes may serve to dampen the effects of external perturbations 2423


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Figure 9. (a) Chemical structure of UPy-1 hydrogelator. X = length of alkyl spacer to create the appropriate hydrophobic pocket; Z = length of the PEG hydrophilic polymer to ensure water solubility. Variations in X and Z define the mechanical properties of the final network. (b) (Left) Atomic force microscope phase image of UPy-1 (X = C10, Z = 2k), and (right) Cryo-TEM image of UPy-1 (X = C10, Z = 6k). Scale bars are 100 nm. (c) Schematic representation of the supramolecular fiber formation. UPy-1 is in equilibrium with small micelles and elongated fibers. Adapted with permission from ref 208. Copyright 2012 John Wiley and Sons.

Figure 10. (a) Chemical structure of BU-1. (b) Cryo-TEM image of a 1 wt % solution of self-assembled nanorods from BU-1. (c) Chemical structure of BU-2, indicating the hydrophobic pocket and H-bonding motif, which facilitates directional self-assembly. Adapted with permission from refs 211 (a and b) and 214 (c). Copyright 2005 Royal Society of Chemistry (a and b) 2007 American Chemical Society (c).

3.1. H-Bonding Motifs

surrounded by a hydrophobic microenvironment, which shields it f rom water.207 3.1.1. Ureido-pyrimidinone (UPy) Motif. In order to use the UPy moiety for polymerization in aqueous solution, Meijer and co-workers end functionalized polyethylene glycol (PEG) with the UPy units, spaced and shielded by a hydrophobic alkyl pocket and decorated with a urea motif primed for lateral hydrogen bonding (Figure 9c).208 This hydrogelator (UPy-1, Figure 9a) self-assembled into a fibrous transient network (Figure 9b) and was characterized in depth.209 The modular design allows for fine tuning of the material properties by molecular design, and the supramolecular nature allows for a controlled and simple incorporation of bioactivity. Growth factor delivery has been demonstrated after injection of the

The use of hydrogen bonds for the self-assembly of supramolecular polymers has become a dominant strategy ever since the seminal work by Meijer and co-workers in 1997.206 Using the quadruple hydrogen-bonding 2-ureido4[1H]-pyrimidinone (UPy) unit (see below), polymeric materials were assembled, having mechanical properties that until then were exclusively associated with covalent polymers. However, when H-bonding units are transferred to aqueous medium, the solvent competes with the H-bonding array, significantly decreasing the strength and stability of this interaction. To achieve robust supramolecular polymerization in aqueous environment, the H-bonding motif needs to be 2424


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Figure 11. (a) Chemical structure and cartoon assembly representation of BTA-1. a.a. stands for a fluorinated L-phenylalanine extended with an aminobenzoate spacer. (b) Cryo-TEM images of BTA-1 (X = Gd(III)-DOTA, left, X = Gd(III)-DTPA, right). Scale bars are 50 nm. Adapted with permission from ref 218. Copyright 2010 National Academy of Sciences.

by an aliphatic spacer (BU-1, Figure 10a). The polymers assembled into well-defined micellar rods of 9 by 100 nm (Figure 10b), which can be further functionalized by guest molecules bearing the urea motif. Boué and co-workers used the bis-urea motif in supramolecular polymers (BU-2, Figure 10c) that spontaneously self-assemble in a wide variety of solvents ranging in polarity from water to toluene.214 The H-bonding unit was placed in between alkylene spacers that create a hydrophobic environment and thereby stabilize the association in water. Ethylene oxide oligomers were introduced to enhance solubility in water and low-polarity organic solvents. Long rigid filaments are formed in dynamic equilibrium with the monomer in all solvents, though the driving force for self-assembly and the exact filament structure was dictated by the particular solvent. 3.1.3. Benzenetricarboxamide (BTA) Motif. Another well-studied hydrogen-bonding supramolecular motif is based on the N,N′,N″-trialkyl-benzene-1,3,5-tricarboxamides (BTAs), which in nonpolar organic solvents self-assemble cooperatively into helical, one-dimensional stacks via 3-fold hydrogen bonding between the amides.215,216 Several methods have been used to enable polymerization of the BTA motif in aqueous solution. In the Meijer laboratory, the BTA motif was extended with a fluorinated L-phenylalanine and an aminobenzoate spacer (BTA-1, Figure 11a), creating a hydrophobic pocket and also significantly increasing the stability of the assemblies via additional H bonds, π−π interactions, and solvophobic effects. Peripheral hydrophilic metal chelate complexes were intro-

loaded UPy-1 gel in the kidney capsule of rats, and myocardial injection through advanced catheters was demonstrated using the pH gel−sol behavior of the UPy-1 hydrogel.210 Besides the UPy-based system, several other monomers that use the combination of an H-bonding array and hydrophobic pocket to enable polymerization have been reported. With the aim to develop functionalized monomer units that would assemble into chiral assemblies with controlled chain length in water, Meijer and co-workers synthesized bifunctionalized ureidotriazine units connected by a spacer to form a donor− acceptor−donor−acceptor (DADA) self-complementary quadruple hydrogen-bonding array.207 Solubilizing chains at the periphery were used to define the structure and helicity of the polymeric assemblies. The assembly mechanism of this system was analyzed by Brunsveld and co-workers and shown to be dominated by the hydrophobic environment as driving force.61 3.1.2. Bis-urea Motif. The urea motif is a strong Hbonding unit, but an even more powerful motif for supramolecular self-assembly is created when it is used in a bis-urea setting. The bis-urea group can be found as “hard blocks” in thermoplastic elastomers and has been shown to promote gelation in various solvents. The unit can be used as host for molecules containing complementary bis-urea motifs, allowing for (bio)-functionalization. In the framework of this idea, Sijbesma and co-workers reported on the design and synthesis of several amphiphilic molecules.211−213 In order to minimize the competing interactions of urea with water and poly(ethylene oxide) (PEO), the bis-urea groups were placed at the center of the nonpolar block and separated from a PEO block 2425


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Figure 12. (a) Chemical structure of BTA-2, displaying the variations in side chains. Cryo-TEM image of BTA-2 in water shows the assembly into long fibers, scale bar = 100 nm. Adapted with permission from ref 219. Copyright 2013 The Royal Society of Chemistry. (b) Chemical structures of chiral BTA-4 variations. Adapted with permission from ref 73. Copyright 2015 Nature Publishing Group. (c) Schematic representation of BTA-2 fibers with BTA-3 fluorescent “guests” that can be clustered via an ssDNA strand. Adapted with permission from ref 220. Copyright 2013 National Academy of Sciences. (d) BTA-2 and BTA-3 structures and schematic overview of the mixing experiment. Cy3-only and Cy5-only fibers were assembled and visualized with stochastic optical reconstruction microscopy (STORM). Upon mixing the fibers, a fast exchange of the fluorescent BTA-3 monomers was observed. Scale bars are 1 μm. Adapted with permission from ref 221. Copyright 2014 The American Association for the Advancement of Science.

2, Figure 12a).219 The compound was shown by TEM to selfassemble into long narrow fibrillar aggregates. The water-soluble BTA unit was subsequently used to demonstrate superselectivity by coassembling neutral BTA-2 monomers with cationic species (BTA-3), where two of the side chains bear primary amine termini (which are positively charged at neutral pH) and a cyanine dye (Cy3 or Cy5, both bearing one positive charge) as a fluorescent label (Figure 12c).220 Single-stranded DNA (ssDNA) was used as the multivalent, polyanionic recruiter necessary to template the

duced to increase the ionic character of the amphiphiles and to transform the resulting molecule into a supramolecular contrast agent for magnetic resonance imaging.217 The self-assembly process was shown to be switchable from long fibers to small discrete objects (Figure 11b).218 Recently, the BTA motif was redesigned by creating a hydrophobic pocket with aliphatic chains to shield the central hydrogen-bonding unit and providing solubility via hydrophilic ethylene glycol motifs on the periphery of the molecule (BTA2426


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Figure 13. (a) Structure of the multisegmented amphiphile CHT-1. Core interactions and amphiphilic properties can be selectively switched off to change the assembly morphology from tapes to fibers. (b) Schematic depiction and TEM of the tape and fiber morphologies. Scale bars are 100 nm. Adapted with permission from ref 83. Copyright 2011 John Wiley and Sons.

Figure 14. (a) Chemical structure of gelator CHT-2 and schematic representation of fiber network formation. (b and c) Two of the custom masks used for light-triggered gel patterning. (d and e) Microscopy images of the gel patterns after irradiation through the masks; scale bars 500 μm. (f and g) Close up of the features; scale bars 100 μm. Adapted with permission from ref 225. Copyright 2014 John Wiley and Sons.

equilibrium dynamics in water-soluble supramolecular polymers. Another example of water-soluble BTAs in functional assemblies is the use of BTA functionalized with an L- or Dproline moiety, displaying high catalytic activity toward aldol reactions in water.222 High turnover frequencies (TOF) of up to 2.7 × 10−3 s−1 and excellent stereoselectivity were observed. The selectivity is the result of the helicity of the supramolecular polymer together with the configuration of the prolines. This study demonstrates how supramolecular assemblies can function as enzyme mimics. Building on these findings, the Lproline BTA system was further developed into a copolymer using structurally similar but functionally inactive BTA units.223 This allowed for assessment of L-proline density versus activity

assembly of cationic BTA-3 receptors and induce their clustering. This control over the spatiotemporal distribution of monomers in a supramolecular aggregate is an important step toward the design of responsive functional systems, and demonstrates that BTA-based supramolecular polymers are versatile tools for molecular recognition. The monomer exchange of the dye-labeled BTA molecules in the selfassembled fibers was elegantly visualized using super-resolution microscopy, exhibiting an unexpected homogeneous distribution of dye molecules within the fibers (Figure 12d).221 A follow-up study with a chiral BTA derivative (BTA-4, Figure 12b) showed that the chiral fibers were more “brittle”, and chiral regions were considered as weak points where local fiber breaking could happen.73 This work is pioneering in the observation of a structure/property relationship with regard to 2427


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Figure 15. Self-assembly of the rosette structure from six monomers through 18 H bonds (left), and the arrangement into helical nanotubes (center). Negatively stained TEM image of the nanotubes (right). Scale bar: 40 nm. Adapted with permission from ref 227. Copyright 2002 National Academy of Sciences.

in the light-exposed region of the sample. Gel micropatterns on surfaces were prepared using custom-made masks (Figure 14b− g). Such light-controlled catalytic pattern formation promises to become a new technique for applications ranging from microfluidics to tissue engineering. Fenniri and co-workers reported on the supramolecular polymerization of monomers displaying an organized array of H bonds, forming “helical rosette nanotubes” (Figure 15).226 The monomers consist of a hydrophobic base that contains the Watson−Crick H-bond donor−donor−acceptor (DDA) motif of guanidine and the acceptor−acceptor−donor (AAD) motif of cytosine. The spatial arrangement constrains the monomers to form a six-membered supermacrocycle (rosette). To minimize peripheral access of water and impose the formation of an intramolecular H bond, a methyl group and an ethylene spacer unit were introduced. The self-assembled rosette is maintained by 18 hydrogen bonds and further self-assembles into a helical supramolecular tube via an entropy-driven process (Figure 15).227 The chirality of the resulting assembly can be defined via the attachment of an amino acid moiety in the monomer228 or by changing the solvent composition.229 The stability of the rosette nanotubes can be tuned by changing the synthetic strategy that yields variations in the monomer preorganization.230 An RGDSK (Arg-Gly-Asp-Ser-Lys)-modified rosette nanotube hydrogel composite was developed and analyzed for application in bone tissue regeneration.231 The rosette hydrogel showed increased fibronectin adsorption and demonstrated a 200% increase in osteoblast adhesion. Modification of the monomer unit into a tricyclic structure by fusing the guanine and cytosine to an internal pyridine ring yielded the self-assembly of hexameric rosettes with an increased inner/outer diameter and very large molar ellipticity (4 × 106 deg M−1 m−1).232 The π-system present in this new family of self-assembled tubes allows for enhanced intermodular electronic communication. Finally, Kieltyka and co-workers recently explored the synergy of aromatic gain and hydrogen bonding in supramolecular polymerization.233 The designed bis(squaramide) bola-amphiphiles could engage in both hydrogen bonding and aromatic stacking. The synergy of these two forces resulted in an increase in thermodynamic stability and yielded different morphological aggregates. Gaining aromaticity as a driving force and design consideration for supramolecular polymerization is anticipated to broaden the palette of future monomer design.

and selectivity. The system proved to be active in catalyst concentrations down to 0.1 mol %. Lloyd and co-workers reported on a series of peripheral aromatic carboxylic acid BTA modifications that allowed for the assembly of a variety of hydrogels.224 The compounds showed spontaneous nucleation and one-dimensional growth resulting from the molecules stacking into fibers through π−π interactions and amide−amide hydrogen bonding. The various gel networks were characterized and showed gelation concentrations of 0.1−0.2 wt %. 3.1.4. Other H-Bond-Driven Polymers. Many processes in molecular biology include morphological transitions, for instance, the cargo vesicles formed by the Golgi apparatus bilayer and chaperone-assisted protein folding. Van Esch and co-workers reported on a supramolecular system wherein morphological transitions were programmed by separately addressing the complex aggregation behavior of different groups.83 As a model system, the authors prepared a multisegment amphiphile (CHT-1, Figure 13a), which consists of two covalently linked orthogonally self-assembling building blocks. The core of the molecule is a 1,3,5-cyclohexyltrisamide hydrogelator, functionalized with three hydrophobic phenylalanine amino acids and tetraethylene glycol tails. This block was coupled to a surfactant segment based on tetraethylene glycol mono-octyl ether, which by itself self-assembles into micelles above a critical micelle concentration. The resulting amphiphilic molecule assembles into long fibers or tapes (Figure 13b). By the addition of a molecular chaperone the selfassembly of the individual segments can be controlled, providing control over morphological transitions within the multisegment amphiphiles. This ability to program and control morphological transitions using molecular chaperone analogues offers new opportunities for the development of smart materials, in which an external trigger induces a morphological transition, altering the macroscopic properties of the material. Recently, van Esch, Eelkema and co-workers reported on the spatial control over supramolecular polymerization by using a visible light-triggered catalyst (merocyanine) to locally initiate hydrogelation.225 Thus far, no detailed mechanism for the polymerization itself has been disclosed; however, it is triggered via light-driven transition of merocyanine into its spiropyran form. This photoisomerization initiates the release of protons; the resulting local pH drop catalyzes the spatially confined condensation of aromatic aldehydes with trishydrazide, thus forming the tris-hydrazone monomer (CHT-2, Figure 14a), which subsequently undergoes supramolecular polymerization 2428


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Figure 16. Compound families PDI-1 and PDI-2 and their supramolecular polymers in aqueous media. PDI-1a forms short supramolecular rods (TEM image, top), whereas a mixture of PDI-1a with PDI-2 results in long, bundled supramolecular fibers (AFM image, bottom). Adapted with permission from refs 82 and 249. Copyright 2007 American Chemical Society and 2015 Nature Publishing Group.

3.2. Large π-Conjugated Surfaces

molecules, focusing on supramolecular polymers that are robust, have interesting thermodynamic or kinetic properties, enable rational polymer design, or advance functional applications. 3.2.1. Perylene Dyes. Perylene dyes are promising building blocks for functional molecular and supramolecular systems.243−246 Perylene diimide (PDI) is a particularly interesting member of this family: it exhibits strong absorption of visible light, high fluorescence quantum yield, photostability, and stability under harsh chemical conditions and high temperature. Importantly, PDI undergoes strong stacking interactions in various media, especially in water.247 For instance, Lewis and co-workers showed that a single PDI−PDI interaction provided sufficient thermodynamic driving force to construct a supramolecular polymer from PDI-capped ds-DNA molecules (Ka = 3.2 × 107 M−1).248 Moreover, the system’s polymerization kinetics were remarkably fast (k+ = 3.2 × 107 M−1 s−1 and k− = 1.0 s−1 in 100 mM NaCl). Several studies have shown that amphiphilicity, spontaneous curvature, and hydrophobic surface area govern the supramolecular polymerization of PDI derivatives in water.45,249,250 Würthner and co-workers made tremendous contributions to the study of PDI self-assembly, providing mechanistic understanding and suggesting various potential applications;251,236,252,253 for instance, dumbbell-shaped PDI derivative PDI-1a was described,249 which forms columnar stacks in aqueous solution (Figure 16). With increasing concentration, these stacks further assemble and align to form supramolecular ribbons.253 Notably, the presence of triethylene glycol groups on both ends of PDI-1a is crucial for its polymerization. The absence or exchange of these hydrophilic moieties alters the molecule’s spontaneous curvature, resulting in the formation of micellar and vesicular structures rather than linear polymers. Remarkably, the strength of intermolecular binding between PDI-1a molecules in water (Ka > 108 M−1) significantly exceeds

The self-assembly of π-conjugated molecules in various solvents has been extensively studied and reviewed.234−239 In aqueous media, large, planar, and uncharged π-conjugated surfaces have the following features, which confer advantages for the rational design and functionality of supramolecular polymers.14,9 (1) Robustness: Self-assembly of π-conjugated systems in water can be extremely strong, due to a combination of hydrophobic and π−π interactions. The driving force of aggregation grows approximately linearly with increasing size of the hydrophobic surface (cf. section 1.3) and results in the formation of exceedingly stable polymers. (2) Order: Unlike long aliphatic chains, which have many degrees of conformational freedom, large π-conjugated systems are rigid and tend to form well-ordered columnar stacks in which steric and electrostatic55 properties of the molecules dictate the precise intermolecular orientations. (3) Electronic coupling: Stacking interactions are accompanied by coupling between the molecules’ delocalized πelectrons. Such coupling may cause interesting optical and electronic properties, such as exciton transport and semiconductivity.240,241 These emergent properties could enable various applications in the areas of sensing, light harvesting, and solar energy conversion. (4) Quantification: π-Conjugated molecules absorb (and sometimes emit) light in the UV/vis or near-IR rage, and their spectral properties are sensitive to aggregation. Therefore, spectroscopic techniques enable facile detection and quantitative investigation of the polymerization process. Spectroscopic techniques can also enable discrimination between different stacking motifs (H vs J aggregation).242 We discuss here selected examples of large π-conjugated molecules, such as derivatives of perylene and other aromatic 2429


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Figure 17. Molecular structures of PDI-3 derivatives, and schematic illustration of the pathway-dependent supramolecular polymerization of PDI-3c. Adapted with permission from ref 30. Copyright 2011 John Wiley and Sons.

Figure 18. Structure of PDI-4, and cryo-TEM image of its tubular supramolecular polymer in water/THF mixture. Adapted with permission from ref 257. Copyright 2015 American Chemical Society.

predictions derived from the linear relationship between solvent polarity and binding energy.252 This observation underlines the complicated role of hydrophobic interactions, which are not merely an effect of solvent polarity. Columnar π-stacks were also observed in structurally related PDI bolaamphiphiles, where a spermine (PDI-1b)250 or a cyclodextrin-derivative (PDI-1c)254 represented the solubilizing groups. Since PDI is electron deficient, it can facilitate the formation of alternating electron-donor/acceptor arrays when mixed together with electron-rich π-conjugated molecules. Rao and George showed that positively charged bolaamphiphile PDI-1d coassembled with a negatively charged oligo(phenylenevinyl-

ene) (OPV) bolaamphiphile to create alternating supramolecular copolymers of the form (AB)n.255 The resulting fibers formed a hydrogel above a critical concentration of 3.3 mM. Moreover, the fiber’s electrical conductivity may enable various applications in molecular electronics. Notably, Würthner and co-workers recently reported the coassembly of PDI-1a with a second PDI amphiphile, PDI-2.82 The bulky aryloxy groups of PDI-2, attached to the molecule’s “bay area”, significantly twist its π-conjugated plane and cause anticooperative aggregation thermodynamics, where the growth of a homopolymer is strongly inhibited beyond the size of dimers. When mixed together, PDI-1a and PDI-2 create 2430


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assemblies that are different from their individual components. The coassembling mixture forms long, bundled nanofibers that contain both PDI-1a and PDI-2. On the basis of microscopic observations, NMR, and optical spectroscopy, this coassembly was proposed to be a supramolecular block copolymer of the form (PDI-1amPDI-22)n, where m and n depend on the concentration and stoichiometry of the mixture. Besides its intriguing supramolecular structure, the system exhibits pathway-dependent behavior. For instance, when the polymer is heated above a critical concentration, component PDI-2 irreversibly precipitates and a homopolymer of PDI-1a is obtained alongside the precipitate of PDI-2. The study exemplifies how noncovalent synthesis is advancing toward kinetically controlled and increasingly complex supramolecular polymers. The group of Rybtchinski explored a number of strategies to enlarge the hydrophobic surface of PDI derivatives, with the goal of developing a rational design of exceptionally stable supramolecular polymers with interesting mechanistic or functional properties (PDI-3, PDI-5, PDI-6, PDI-7, PDI8).14,15,9 The PDI-3256,30 family contains a terpyridine (terpy) group, which enables facile modification of the molecule via coordination chemistry (Figure 17). Interestingly, PDI-3c forms multiple polymer species, two of which are metastable states and the third is considered to be the thermodynamically equilibrated system; each of these distinct polymer morphologies are prepared via a specific assembly pathway or via conversion from a less favorable state. While large kinetic barriers can complicate polymer design and preparation, they also enable the generation of structurally diverse polymers from a single molecular building block. Thus, nonequilibrium hydrophobic self-assembly represents a challenge as well as an opportunity for aqueous supramolecular polymerization. Hirsch and co-workers recently reported amphiphile PDI-4, describing kinetic effects that are very similar to those observed in PDI-3c. Analogous to PDI-3c, PDI-4 can form multiple coexisting, kinetically trapped supramolecular assemblies, including platelets and long tubular polymers (Figure 18).257 The two PDI groups of PDI-4 can undergo both intra- as well as intermolecular π-stacking. In the absence of an organic cosolvent, large kinetic barriers appeared to impede morphological transformations on the laboratory time scale, even when the system was annealed at 85 °C for several hours. However, in the presence of THF, the metastable tubular structures were transformed into platelets and the material eventually precipitated from solution. High polymer stability may be achieved via the use of fluorinated alkyl groups (F-alkyl), which are significantly more hydrophobic than their nonfluorinated analogs.258 To test this strategy, Rybtchinski and co-workers studied the supramolecular polymerization of compound PDI-5a,45 which is decorated with a perfluoro-octyl chain (Figure 19). To directly measure polymerization thermodynamics, the hydrophobic interactions had to be attenuated by the addition of at least 25% THF (v/v), where the system still showed a remarkable association constant of Ka = 1.7 × 109 M−1. In solutions containing ≥95% water the polymer could not be disassembled, even at nanomolar concentrations and temperatures close to the boiling point. In pure water, the association constant of PDI-5a was estimated to be at least in the order of 1015 M−1, which is 3 orders of magnitude higher than for its nonfluorinated analog PDI-5b. The hydrophobic and steric properties of the F-alkyl

Figure 19. Molecular structure of PDI-5 derivatives, as well as cryoTEM image and molecular model of the supramolecular polymer fibers formed by PDI-5a. Adapted with permission from ref 45. Copyright 2014 American Chemical Society.

also resulted in surprising cooperative effects, accompanied by cosolvent-dependent morphological transformations. Bolaamphiphiles PDI-665,259 and PDI-7260 comprise the combined hydrophobic surface of two PDI groups (Figure 20, Figure 21). Both PDI-6a and its larger analog PDI-7 form hierarchically assembled, segmented, supramolecular polymer fibers that are up to several micrometers long. Because of their extended hydrophobic cores, organic cosolvent or longer PEG chains (PDI-6b) are required to disperse the fibers in aqueous solutions. Interestingly, PDI-6b can form several distinct kinetic polymer products in pure water without organic cosolvent. Unlike PDI-3c, however, these “supramolecular polymer isomers” are so stable that they cannot be converted into each other by annealing, even when heated to 100 °C for prolonged periods of time. Due to different stacking motifs, the polymer isomers also strongly differ in their spectroscopic and electronic properties. In the presence of organic cosolvent, the kinetic barriers between different PDI-6b polymer isomers become smaller and the polymer transformations become experimentally accessible. In water/THF (3:2, v/v) the transformation was shown to involve a nucleation/growth process with rate constants for nucleation, knuc, and growth, k+, of 8.2 × 10−2 and 3.92 × 103 s−1, respectively, revealing a significant activation barrier for polymer transformation of 77.8 kJ/mol (at 20 °C).34 The transformation between the two polymer isomers appears to proceed without complete detachment of monomer molecules, involving an internal reorganization of monomer units within the polymer fibers rather than a dissociation/reassociation process. Despite being exceptionally stable, both PDI-6 and PDI-7 can undergo reversible depolymerization, triggered by chemical redox reagents (e.g., oxygen and sodium dithionite). Notably, high concentrations of PDI-7 polymer fibers lead to the formation of a supramolecular gel. This soft material can rapidly change its volume and mechanical and optical properties in response to multiple external stimuli. Moreover, the gel could 2431


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Figure 20. Molecular structure of PDI-6 derivatives and cryo-TEM images, illustrating reversible depolymerization triggered by chemical redox agents. Adapted with permission from ref 259. Copyright 2008 American Chemical Society.

cosolvent (THF), the association constant was very high (Ka = 8.2 × 108 M−1). Notably, the molecular geometry prevents continuous columnar stacking of PDI groups. However, the number of pairwise intermolecular PDI−PDI contacts is maximal in a linear arrangement of molecules, where three PDI groups noncovalently bind three PDI groups of the adjacent monomer, due to a specific positioning of PDI units, enabled by a 1,3,5-triethylbenzene scaffold. Thus, although hydrophobic interactions are inherently nondirectional, geometric constraints can encode the directionality of hydrophobically driven supramolecular polymerization. To demonstrate a practical material application of an aqueous supramolecular polymer, Rybtchinski and co-workers used PDI-7 to fabricate a new type of ultraf iltration membrane (Figure 23).16 Membranes of a desired thickness were prepared by aqueous self-assembly and subsequent deposition of the polymer dispersion on a cellulose acetate support (Figure 23a and 23b). The membranes comprised a compact network of entangled polymer fibers (Figure 23c−e), which resisted pressure-driven flux of aqueous solutions, without detectable leaching of PDI-7 into the solution. Thin membranes were used for filtration and chromatographic separation of metal and semiconductor nanoparticles (Figure 23f and 23g). Moreover, the membranes were used to separate proteins under physiological conditions and to immobilize large enzymes for the construction of biocatalytic membrane reactors. 262 Importantly, the supramolecular material can be disassembled under mild conditions via reversible depolymerization (e.g., using a water/ethanol mixture). This way, retained particles can be released on demand and the used membrane can be fully recycled (Figure 23h). The membrane permeance (1.1 × 102 l h−1 m−2 bar−1) was comparable to commercial membranes with similar rejection properties. The findings indicate that supramolecular polymers can offer robustness, advantageous adaptivity, and functionality for applications that are currently dominated by classical (covalent) materials. Stupp and co-workers recently reported a functional supramolecular polymer that is based on perylene monoimide

Figure 21. Molecular structure of PDI-7, and cryo-TEM (left) and cryo-SEM (right) images of its supramolecular polymer fibers in water/THF mixture. Adapted with permission from ref 260. Copyright 2009 American Chemical Society.

be used as a light-harvesting scaffold, as the entangled polymer fibers (Figure 21) absorb a wide spectrum of visible light and facilitate photoinduced energy transfer. PDI-8261 is currently the largest PDI-based molecular building block for aqueous supramolecular polymerization (Figure 22). The combined molecular surface of six PDI units leads to exceedingly strong hydrophobic binding. The large driving force prevented thermodynamic characterization in pure water, but even in the presence of 30% disaggregating 2432


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Figure 22. Molecular structure of PDI-8; cryo-TEM image and a molecular model of its supramolecular polymer fibers. Adapted with permission from ref 261. Copyright 2011 American Chemical Society.

fluorescence in the aggregated state. Above the critical concentration of 0.8 wt %, the supramolecular fibers aligned and entangled, forming a nematic hydrogel. The gel was responsive to temperature changes and underwent a reversible gel−sol transition upon cooling (Figure 25d). Changing the temperature from 10 to 30 °C enabled the rapid transition between solution and the gel state; rheological experiments confirmed a temperature-triggered change of the elastic modulus by 1 order of magnitude. These thermoresponsive properties were attributed to the well-known temperatureinduced dehydration of the molecule’s oligoether dendrons. Importantly, the gel is biocompatible and can be used as an artificial scaffold for cell cultures, mimicking a function of the extracellular matrix. On demand, the gel can be liquefied via cooling, thus releasing the entrapped cells. The biocompatibility and stimuli responsiveness of the polymer makes it well suited for applications related to tissue engineering and controlled drug release. Figure 26 shows two bent-shaped molecules, BA-1 and BA-2, which were also reported by the Lee group. Both compounds form tubular supramolecular polymers that exhibit interesting stimuli-responsive properties, such as temperature-responsive inversion of tubular helicity.269,17,270 At 0.01 wt % BA-1 forms supramolecular fibers, which are several hundreds of nanometers long. BA-2 is furnished with a larger hydrophilic dendron and exhibits significantly shorter polymer fibers, which are only a few tens of nanometers long; this inhibited polymer growth is presumably a consequence of steric repulsion between the dendrons. The nanofibers of BA-1 and BA-2 could be used as a host to encapsulate up to one equivalent of poorly watersoluble p-phenylphenol. The uptake of this guest is accompanied by distinct changes in the absorption spectrum, strongly increased CD intensity, and a structural transformation from 5 nm wide compact polymer fibers to 8 nm wide fibers

(PMI) amphiphile PMI-1 (Figure 24).19 The polymer fibers have a ribbon-like structure, comprising tightly stacked PMI groups (Figure 24e). Upon addition of salts, the fibers further assemble to form crystalline sheets, resulting in gelation at high concentration, accompanied by pronounced changes in the compound’s absorption spectrum (Figure 24c). When illuminated with visible light, electronic coupling between the PMI units may facilitate transport of excitation energy. Importantly, the polymer fibers can electrostatically bind a positively charged nickel complex that acts as a catalyst for hydrogen reduction. In the presence of ascorbic acid as a sacrificial electron donor and proton source, the catalyst-infused gel performs photocatalytic production of H2 with a turnover number (TON) of up to ∼340 at a turnover frequency (TOF) of 19 h−1. The presence of both catalyst and sacrificial electron donor is vital for the material’s photocatalytic activity (Figure 24d). Notably, the strongly hydrated nanoscopic gel structure, with its large internal surface, resulted in significantly stronger photocatalytic activity relative to that of its dried precipitate. PMI-1 exemplifies that hydrogels formed from perylene-based supramolecular polymers can be utilized for the conversion of solar energy into high-energy fuels. 3.2.2. Rigid Aromatic Rod- and Bent-Shaped Amphiphiles. Rigid rod- and bent-shaped amphiphiles have been intensively studied in the context of aqueous supramolecular polymerization.235,263 The group of Lee reported numerous supramolecular systems, demonstrating stimuli-responsive morphological transformations,264 temperature-induced supramolecular chirality and gelation,265 biologically relevant functions,266 and more.267 Lee and co-workers also reported on a biocompatible supramolecular polymer based on the aromatic penta-p-phenylene rod amphiphile PPR-1 (Figure 25a and 25c).268 The polymer fibers were composed of J-stacked PPR-1 molecules (Figure 25b), which retained strong 2433


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Figure 23. Supramolecular membrane based on PDI-7. (a) Simple fabrication of the membrane by deposition of polymer fibers on a cellulose acetate support membrane. (b) Photograph of the supramolecular membrane. (c−e) Cryo-SEM images of the membrane’s cross-section at different magnifications, revealing an entangled network of supramolecular fibers. Application of the membrane for filtration (f) and size-selective fractionation (g) of metal and semiconductor nanoparticles. (h) Scheme of fabrication, use, and recycling of the supramolecular membrane. Adapted with permission from ref 16. Copyright 2011 Nature Publishing Group.

reported by the same group,271 NDPA forms helical supramolecular structures in aqueous buffer in the presence of an adenine nucleotide (ATP, ADP, or AMP; Figure 28a). Interestingly, detailed circular dichroism (CD) studies showed that the handedness of the supramolecular NDPA fibers not only depended on the adenine nucleotide during assembly but also underwent fast switching in response to competitive replacement of AMP or ADP by ATP. The CD signal of the helical supramolecular fibers could thus be used to monitor the kinetics of enzymatic ATP hydrolysis. Such supramolecular detection could find application in sensing of various cellular processes related to ATP energy consumption. The group of Häner reported several supramolecular polymers composed of phosphodiester-linked chromophore oligomers.272−276 For instance, phenanthrene oligomer PO-1 self-assembles when cooled from 90 °C to room temperature (Figure 29).275 The columnar π-stacking of interdigitating phenanthrene groups created extended supramolecular polymer fibers several micrometers in length (Figure 29c). Coassembly of PO-1 with small amounts of the pyrene-containing oligomer PO-2 led to the formation of pyrene-doped supramolecular polymers. While the polymer that contained exclusively PO-1 only exhibited weak fluorescence, the pyrene-doped polymer showed strong pyrene fluorescence upon phenanthrene excitation, indicating that pyrene acts as an energy acceptor

that appear to be tubular. The authors propose that pphenylphenol is encapsulated in the fiber via multiple noncovalent interactions (including an H bond with the amphiphile’s pyridine group), which triggers reversible inflation of the fiber. Fernandez and co-workers recently described the dumbbellshaped oligo(phenylene ethynylene) (OPE) amphiphile OPE-1 (Figure 27), which forms supramolecular polymers in various polar solvents, including water.62 At high concentrations, OPE1 fibers further entangle and generate a supramolecular gel in water or alcohol. In pure water, the supramolecular polymer is robust enough to thwart studies into its thermodynamic properties. However, in water/methanol mixtures, the noncovalent interactions are sufficiently attenuated to enable reversible temperature-dependent depolymerization. The investigation revealed cooperative polymerization and an association constant for polymer elongation of 8 × 103 M−1 in water/methanol (3:7, v/v). The authors suggested that in addition to π−π and solvophobic interactions, multiple unconventional H bonds play a key role in the supramolecular polymerization of OPE-1. 3.2.3. Other Systems. George and co-workers reported a supramolecular polymer based on a naphthalene diimide (NDI) group, furnished with two zinc coordination sites (NDPA, Figure 28).20 Much like a PDI analog that had been previously 2434


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Figure 24. Supramolecular polymer based on a PMI amphiphile. (a) Molecular structure of PMI-1. (b) Cryo-TEM image of the supramolecular polymer, revealing ribbon-like fibers with high aspect ratios. (c) Absorption spectra of the supramolecular polymer solution and gelled samples. (d) Hydrogen production only takes place when the light-absorbing supramolecular polymer gel, nickel catalyst, and sacrificial electron donor are combined and illuminated. (e) Molecular model of the polymer ribbon. Adapted with permission from ref 19. Copyright 2014 Nature Publishing Group.

ization can be utilized to construct linear light-harvesting antennae with dynamic properties. Coronene is a C6-symmetric molecule comprising the hydrophobic surface of six fused benzene rings. George and co-workers prepared coassemblies of a coronene-based amphiphile (CS-1) and electron-poor viologen derivatives (V1) (Figure 30).277 Charge-transfer interactions between CS-1 (electron donor) and V-1 (electron acceptor) governed the formation of 1:1 complexes, which grew into long, onedimensional π-stacks. The 1:1 complex of CS-1 with V-1c comprises a charged “head” of stacked coronene/viologen groups and a hydrophobic dodecyl group, thus representing a supramolecular amphiphile. Interestingly, the assembled CS-1/ V-1c polymer fibers entangled and formed bundles, resulting in the formation of a hydrogel above a critical concentration of 8 mM. CS-1/V-1c nanofibers facilitated charge transfer along the fiber axis, enabling various electronic applications. Indeed, in a subsequent study Kulkarni and co-workers demonstrated that it is possible to use these supramolecular fibers to fabricate inexpensive high-mobility field-effect transistors via solution processing.278 Hexabenzocoronene (HBC) is another class of large πconjugated surfaces. It is a C6-symmetric extension of coronene and has properties that are suitable for various (opto)electronic applications.279,280 Müllen and co-workers synthesized several HBC derivatives that were functionalized with hydrophilic groups and showed that they formed well-ordered columnar stacks in aqueous solution and in the liquid crystalline phase.281,282 Aida and co-workers reported uncharged HBCbased molecules that produced tubular structures in various organic solvents.283 The same group later synthesized HBC amphiphiles that were endowed with positively charged isothiouronium groups.284 In dichloromethane (DCM) HBC1 polymerized into nanotubes (Figure 31). Despite the presence of charged groups, HBC-1 did not dissolve directly

Figure 25. Thermoresponsive hydrogel based on a supramolecular polymer. (a) Molecular structure of aromatic rod amphiphile PPR-1. (b) Schematic illustration of supramolecular polymerization. (c) CryoTEM image of supramolecular fibers. (d) Photograph of solution (left) and gel state (right). The gel/sol transition is triggered by temperature changes. Adapted with permission from ref 268. Copyright 2011 Nature Publishing Group.

when phenanthrene groups in its vicinity are photoexcited. The presence of 0.015 equiv of pyrene was sufficient for nearcomplete transfer of photoexcitation energy, and the average energy transport distance was estimated to be roughly 150 nm. This finding revealed an efficient energy transport mechanism that is likely enabled via the tight π-stacking of chromophores in the polymer fibers. Consistently, the energy transfer can be switched on and off via thermal (dis)assembly of the polymer fibers. This study exemplifies how supramolecular polymer2435


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Figure 26. Bent-shaped amphiphiles BA-1 and BA-2 forming supramolecular polymers. When p-phenylphenol is added the fibers inflate and form tubular structures that host p-phenylphenol guest molecules. Adapted with permission from ref 270. Copyright 2014 American Chemical Society.

Figure 27. Structure of OPE-1.

Figure 28. Supramolecular polymer that inverts its helical handedness in response to competitive exchange of adenine nucleotides. (a) Molecular structure and schematic supramolecular models of the helical polymers. (b) Change of the circular dichroism signal during enzymatic hydrolysis of ATP. Reprinted with permission from ref 20. Copyright 2014 Nature Publishing Group.

in water, even when heated to reflux. However, its supramolecular nanotubes could be transferred to aqueous solution from DCM via stepwise solvent exchange. After being transferred to aqueous solution, the nanotubes retained their rigid nanotubular morphology (Figure 31b−d) and remained uniformly dispersed. Such pathway-sensitive self-assembly represents another example for the effect of large kinetic barriers, as described for various supramolecular polymers involving large π-conjugated surfaces (vide supra). The isothiouronium groups of HBC-1 not only were essential for efficient dispersion in water but also enabled noncovalent functionalization of the assembled tubes in aqueous solution: for instance, when the tubes were mixed

with a solution of poly(4-styrenesulfonate) (PSS), robust multivalent binding between oppositely charged H-bonding isothiouronium and PSS resulted in a hybrid covalent polymer/ supramolecular polymer material. Exploiting the same noncovalent isothiouronium/oxyanion binding motif, the nanotubes were also functionalized with anthraquinone-2-carboxylate (AQ). These modified polymers exhibited quenched fluorescence, likely as a result of photoinduced electron transfer to the electron acceptor, AQ. The tubes thus demonstrate a promising approach for noncovalent postmodification as a method for versatile generation of functional supramolecular polymers. 2436


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Figure 29. Supramolecular polymer based on phenanthrene oligomer PO-1 and pyrene-containing dopant oligomer PO-2. (a) Molecular structures. (b) Schematic assembly of interdigitating π-stacks. (c) AFM image of supramolecular fibers. Adapted with permission from ref 275. Copyright 2014 John Wiley and Sons.

Figure 30. Molecular structure of an electron-rich coronene tetracarboxylate salt, CS-1, and electron-poor viologen derivatives, V-1, which form alternating supramolecular copolymers when coassembled at a 1:1 molar ratio.

Polymerization of π-conjugated amphiphiles can be controlled via the use of ssDNA.285−287 In this approach, the DNA strand binds to the amphiphiles via H bonding and thus templates polymer growth. For example, Schenning and coworkers used oligothymidine strands (dTn; n = 10 or 40) to control the polymerization of π-conjugated amphiphiles NT-1 and OPVT-1 (Figure 32).288,289 Both molecules contain a diamino triazine group as a recognition site that provided specific H bonding with the thymine groups of dTn. Thus, in the presence of dTn, self-assembly of NT-1 and OPVT-1 resulted in chiral supramolecular stacks. In the right concentration regime, this approach can potentially afford supramolecular polymers with well-defined length and optoelectronic properties. Meijer and co-workers reported a large π-conjugated amphiphile comprising four OPV groups that were attached to one central porphyrin unit.290 In aqueous solution, selfassembly of these amphiphiles resulted in formation of chiral supramolecular polymer fibers. In coassemblies with their corresponding zinc complexes, transfer of photoexcitation energy from the OPV groups to the central porphyrin−Zn complex and further energy transfer to a free porphyrin group

Figure 31. Supramolecular nanotubes based on amphiphilic hexabenzocoronene (HBC). (a) Molecular structure of HBC-1. (b) Schematic depiction of the tubular structure and proposed structure of the tube wall. (c) SEM and (d) TEM images of HBC-1 nanotubes. Adapted with permission from ref 284. Copyright 2007 American Chemical Society. 2437


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Figure 32. Schematic depiction of ssDNA-templated supramolecular polymerization, and molecular structures of oligothymidine dTn, naphthalene amphiphile NT-1, and OPV amphiphile OPVT-1. Reprinted with permission from ref 288. Copyright 2007 American Chemical Society.

controlling the formation of directed supramolecular polymers has become a major focus in supramolecular chemistry. The mechanism of polymerization and the resulting polymer properties are defined by the strength and nature of the HG unit. By mixing several HG complexes, increasingly complex systems can be assembled in a directed and ordered fashion. Below, we subdivide the discussion of HG systems by the nature of the host, which may be synthetic or biological in origin. Extensive reviews provide greater detail on this topic and should be referred to for in-depth information about the specific examples.11,13,96,99,300−304 3.3.1. Synthetic Host−Guest Systems. Macrocyclic host molecules are highly attractive for use in supramolecular polymerizations, due to their ability to capture a wide range of recognition motifs.301 Of available synthetic host species, crown ethers, hydrophobic calixarenes, and pillararene macrocycles are commonly used to construct hydrophobic supramolecular polymers via hydrogen-bonding interaction in lower polarity solvents, while cyclodextrins, cucurbiturils, and hydrophilic calixarenes-based supramolecular polymers can be formed in aqueous solution.11 Guest molecules that interact with these macrocycles include general organic compounds that can be incorporated inside the host cavity. Supramolecular polymers are constructed by linking guest and host or by producing guest−guest/host−host complexes. Macrocyclic host−guest systems have been extensively reviewed;11,13,99,300−304 therefore, our discussion below is limited to selected examples from the recent literature that illustrate important concepts of polymer design and structure/property relationships. 3.3.1.1. Cyclodextrins. Cyclodextrins (CDs) are cyclic oligomers that are assembled out of six (α), seven (β), eight (γ), etc., glucopyranose units as a result of intramolecular transglycosylation reaction from degradation of starch by the cyclodextrin glucanotransferase (CGTase) enzyme.305 In water, CDs form complexes with a variety of organic guest molecules,

was observed. Notably, this sequential energy transfer occurred within the individual polymer fibers but not across different fibers. Moreover, when coassembling the supramolecular polymers with C60 fullerenes, photoinduced electron transfer to the C60 fullerene was observed. We note that large π-conjugated surfaces can also be generated by dendrimer chemistry.291 For instance, Hecht and co-workers developed supramolecular polymers, which were assembled from disc-shaped π-conjugated dendrimers.292 These polymers showed slow association kinetics and large association constants (e.g., Ka = 1.7 × 107 M−1 for a third-generation dendrimer). While synthesizing large hydrophobic surfaces is a useful approach for the design of robust binding in water, supramolecular polymers can also be obtained from small aromatic molecules, if significantly strong electrostatic interactions293−295 or additional binding motifs296 are harnessed to stabilize the π-stacked assemblies. There is also large interest in conjugates of aromatic monomers with oligopeptide chains.297,298 Supramolecular polymerization of such conjugates can create functional biomaterials with intriguing optoelectronic properties, pertinent to applications related to light harvesting, biosensing, and cell and tissue engineering. These materials are discussed in the context of peptide-based supramolecular polymers (section 3.4). 3.3. Systems Linked by Host−Guest Interactions

Host−guest (HG) systems launched the field of supramolecular chemistry with the discovery of cryptands and crown ethers by Lehn, Cram, and Pedersen.299 As the nomenclature indicates, two moleculesthe host and the guestare involved; these form a specific (and usually strong) supramolecular complex. The host generally contains a cavity that is molecularly recognized by the guest. HG interactions are very selective, because the host molecule imposes multiple restrictions on the guest in terms of size, shape, charge, and polarity. The application of molecular recognition by HG couples for 2438


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Figure 33. Summary of supramolecular polymers that use CD as host. Examples include the following. (a and b) AB-type linear polymers with HG-1 and HG-2. Adapted with permission from ref 310. Copyright 2004 American Chemical Society. (c and d) AA-BB style linear versus cyclic assemblies with HG-3 and HG-4. Adapted with permission from ref 311. Copyright 2005 American Chemical Society. (e and f) Photoswitchable AA-BB linear polymers with HG-5 and HG-4. Adapted with permission from ref 313. Copyright 2007 American Chemical Society.

approach showed various flexibility in their linkers, which affected the degree of polymerization of the building blocks and their arrangement in cyclic (degree of polymerization (dp) = 3−5) or linear structures (dp >30) (Figure 33c and 33d).311 High molecular weight (100 000 Da) linear β-CD polymers were assembled from AA-BB-type monomers spaced by PEG linkers (600 Da).312 Harada and co-workers showed that the use of a stimulusresponsive stilbene moiety in the β-CD dimer unit (HG-5) allows the degree of polymerization of CD polymers to be photochemically controlled.313 In the trans conformation, supramolecular dimers or small assemblies are formed, whereas in the cis conformation high molecular weight supramolecular linear polymers are observed. The affinity for monomeric adamantyl guest molecules in β-CD was similar in either the cis or the trans conformation; however, for the divalent guest

which are specific for the various CDs and display a wide range of binding affinities.306 CDs were first discovered in 1891307 and have since been extensively used in host−guest chemistry.300,306 Key findings on the use of CDs to assemble supramolecular polymers in water come from the group of Harada. Host−guest specificity and selectivity can be used to assemble AB-type supramolecular polymers. Adamantane is a strong guest for the β-CD cavity, with an association constant of 104 M−1, while similar affinities are found for phenol and phenylalanine guests in α-CD.308,309 Conjugation of the β-CD guest to the α-CD ring and vice versa yields building blocks (HG-1/HG-2) that self-assemble into alternating α-CD/β-CD polymers (Figure 33a and 33b).310 Besides AB-type polymers, AA-BB-type polymer assemblies have also been demonstrated using a β-cyclodextrin dimer (HG-3) and ditopic adamantyl guest (HG-4): the ditopic guest dimers prepared through this 2439


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Figure 34. Summary of supramolecular CB[n] host−guest polymeric systems. (a) Chemical representation of the guest structure (HG-6) that prevents 1:1 cyclic species by spacer length and 2:2 cyclic species by charge repulsion between viologen moieties. Reprinted with permission from ref 319. Copyright 2010 John Wiley & Sons. (b) Cucurbit[n]urils and guests bearing two anthracene units (HG-7) form linear polymers via π−π interactions. Adapted with permission from ref 320. Copyright 2011 John Wiley and Sons. (c) Schematic representation of an ABBA-type monomer that contains an azobenzene guest (HG-8) and the corresponding photoswitchable supramolecular polymer. Adapted with permission from ref 323. Copyright 2013 American Chemical Society. (d) FGG peptide guest molecule (HG-9) forms linear polymers with CB[8]. Adapted with permission from ref 325. Copyright 2013 Royal Society of Chemistry. (e) Supramolecular polymers formed by self-sorting using HG-10, CB[7], and CB[8]. Adapted with permission from ref 327. Copyright 2014 John Wiley and Sons.

affinities of 1.45 ± 0.2 × 106 and 4.18 ± 0.3 × 105 M−1 were reported for the trans- and cis-stilbene dimer, respectively (Figure 33e and 33f). The large cavity of γ-CD can include relatively large guest molecules or even two smaller guest molecules together. Binding of two guests simultaneously provides a new strategy for constructing supramolecular polymers, in which the γ-CD host works as a connecting junction for two moieties that belong to different guest building blocks. If the units included in the γ-CD cavity are stimulus responsive, the resulting supramolecular polymer displays responsive behavior.314

3.3.1.2. Cucurbiturils. Cucurbiturils (CBs) represent another class of cyclic host molecules; they are macrocyclic methylenebridged glycoluril oligomers whose shape resembles a pumpkin (hence the name). They contain an ureido carbonyl-lined hydrophobic cavity for various guest molecules, including noble gases, alkanes, alkenes, alcohols, carboxylic acids, amines, and positively charged molecules. The first member of this cyclic family was the hexameric CB[6]; since then the cucurbit[n]uril family has grown to include smaller and larger analogues (CB[5]−CB[10]).315 Work on CB[n] has been pioneered by the research groups of Mock, Kim, and Buschmann.315−317 2440


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Figure 35. Examples of aqueous polymers using calixarene as a host. (a) Supramolecular assemblies using a porphyrin guest (HG-11). Adapted with permission from ref 330. Copyright 2009 John Wiley and Sons. (b) Supramolecular polymers with a viologen guest molecule (HG-12). Adapted with permission from ref 332. Copyright 2014 John Wiley and Sons. (c) Assembly of a linear supramolecular ternary polymer (consisting of HG-13, HG-14, and HG-15) using two orthogonal binding motifs with cyclodextrin and calixarene. Adapted with permission from ref 331. Copyright 2012 Royal Society of Chemistry. (d) Light-controlled linear polymerization of HG-16 and HG-17 and TEM imaging of micrometer long linear polymers. Adapted with permission from ref 333. Copyright 2013 American Chemical Society.

A potential limitation of using the CB[n] family in supramolecular polymerizations in water is their relatively poor solubility. CB[6] and CB[8] are virtually insoluble, whereas CB[5] and CB[7] are modestly soluble. However, the solubility of all structures dramatically increases in acidic solution, due to the carbonyl linings of the CB unit. Furthermore, due to the difficulties in modifying CBs, supramolecular polymers based on CB[5], CB[6], and CB[7] are rare. CB[8] is able to bind two guests in its relatively large cavity and thus is the most promising potential host for the selfassembly of supramolecular polymers;318 however, because of the overall poor solubility in water, attempts at linear polymerization using CB[n] have yielded chains of limited length. Linear CB[8] polymers in water have been obtained utilizing the “dimer in dimer” strategy, where the guest is chosen to

prevent both 1:1 intramolecular complexation as well as 2:2 cyclic dimerization. Examples of such guest systems are the ABBA anthracene−viologen−viologen−anthracene molecules (HG-6) reported by Zhang and co-workers (Figure 34a)319 in which the monomer is designed with a short linker to prevent intramolecular complexation and the charge repulsion between the viologen moieties inhibits 2:2 cyclic dimerizations. A similar system from this group uses two anthracene units in the guest (HG-7) to obtain a host-enhanced π−π interaction that stabilizes linear polymers (Figure 34b).320 Scherman and co-workers used CB-based host−guest interactions to cross-link covalent polymers, to noncovalently functionalize the polymer’s periphery, and to construct linear supramolecular polymers.321−323 Using two azobenzene groups (A) and two 4,4′-bipyridinium dications (B), monomers of the type AB-BA (HG-8) were synthesized.323 CB[8] mediated the 2441


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Figure 36. (a) Individual components and proposed assembly mechanisms of the bisMTX (HG-19) and DHFR (HG-18). (b) Negatively stained TEM image of the corresponding distribution of nanoring dimensions. Adapted with permission from ref 339. Copyright 2006 American Chemical Society (a and b). (c) Negatively stained TEM image of oligomeric linear streptavidin fibers. (Inset) Cartoon representation of the designed system. Adapted with permission from ref 344. Copyright 2003 The American Association for the Advancement of Science. (d) Chemical structure of the bis-biotinylated terpyridine guest (HG-20), which forms a linear tetrabiotinylated connector upon reaction with Fe(II). In the presence of streptavidin linear coordination polymers are formed. Adapted with permission from ref 345. Copyright 2007 John Wiley and Sons.

affinity of CB[8] for the naphthalene end groups is ∼105 M−1, and two naphthalene guests fit in the CB[8] cavity. Playing with these variations in guest affinity, upon 1:1:1 addition of the compounds, linear polymers are assembled through self-sorting, where the phenylene groups bind to CB[7], while the naphthalene groups form a dimers within CB[8] (Figure 34e). CB analogues are being developed with the goal of improving water solubility and ease of chemical modification. For instance, Tian and co-workers prepared a new host from propanediurea−formaldehyde condensation328 and reported that the resulting cyclic host molecule is soluble in water as well as in common organic solvents. It binds protonated amines in a 1:2 stoichiometry in H2O, with association constants in the order of 103 M−1. The self-assembly of this new host with 1,4-xylylene diamine dihydrochloride results in the formation of a linear supramolecular polymer with a length of several hundred nanometers. 3.3.1.3. Other Cyclic Host−Guest Systems. Besides cyclodextrins and cucurbiturils several other macrocycles are used to assemble linear supramolecular polymers. For example, calixarenes are cyclic oligomers based on a hydroxylalkylation product of phenol plus an aldehyde.329 Modifying the calixarene rims with hydrophilic groups improves the hydrophilicity and solubility of this oligomer in aqueous media. As with other HG systems, AB-type heteroditopic monomers and AA/BB-type homoditopic monomers yield supramolecular polymers. Liu and colleagues designed a series of water-soluble

formation of heteroternary complexes and supramolecular polymers through host−guest inclusion (Figure 34c). Photoisomerization of the azobenzene moieties from the E to the Z isomer triggered depolymerization, thus forming binary Zazobenzene-CB[8] complexes, as confirmed by 1H NMR and DOSY experiments, as well as static light scattering.323 Pang and co-workers developed a different system that assembles into linear polymers using an orange thiazole dye as a rigid soluble guest.324 The authors found that using different stoichiometric ratios of guest and host yielded linear polymers with both CB[7] and CB[8]. Contrary to these short and rigid monomers, monomers with a flexible but sufficiently long linker can also be used to form supramolecular polymers, a strategy employed by Zhang and co-workers to demonstrate that mixing a bifunctional FGG peptide spaced by an octaethylene glycol linker (HG-9) with CB[8] in aqueous solution yields supramolecular polymers (Figure 34d).325 CB[8] binds two FGG peptides cooperatively with a very high affinity of Ka ≈ 1011 M−2.326 Zhang, Scherman, and co-workers used the difference in guest affinity between CB[7] and CB[8] to design supramolecular polymerizations driven by self-sorting (Figure 34e).327 A bifunctional monomeric guest molecule (HG-10) was synthesized consisting of two naphthalene moieties bridged by a p-phenylene linker. The affinity of CB[7] for the phenylene group is ∼109 M−1, while the guest binds to CB[8] with a lower affinity of around 107 M−1. The binding 2442


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specific synthetic guest candidates, which we can use for host− guest polymerization. Wagner and co-workers used the protein−drug interaction between dihydrofolate reductase (DHFR) (HG-18) and a bivalent methotrexate (bisMTX) (HG-19) to assemble cyclic and linear structures (Figure 36a and 36b).339 The host affinity for MTX is in the order of ∼109 M−1,340 and the complex is further stabilized by protein−protein interactions. The protein was produced in dimeric form using a flexible peptide with different length and composition that defined the diameter of the cyclic structures (8−20 nm). Cross-linking of antibodies generally serves as a first step in their downstream effector functions. For example, cross-linking of immunoglobulin E (IgE) class antibodies is the triggering signal for mast cells to start their degranulation process. Haptens are small molecules that can interact with antibodies to initiate an immune response and can thus be used as guest molecules to link antibody hosts into polymeric structures. Back in 1987, Pecht and co-workers reported on the interaction of a series of divalent dinitrophenol (DNP) haptens with a DNP-specific monoclonal IgE class antibody.341 Following this, a large series of divalent haptens was produced with variations in linker length and rigidity, and the effect of the intrinsic association constant and type of assembly formed (e.g., linear vs cyclic) was studied. Intrinsic hapten-IgE association constants of about 107 M−1 were reported. Many years later, the group of Whitesides reported on a similar system, which was developed as an antibody purification method.342 Polymerization of antibodies with multivalent haptens was used to extract monoclonal antibodies from ascites fluid, and after polymerization, the free antibodies were reobtained. A widely used host−guest couple is the protein streptavidin and its guest biotin. Streptavidin provides four pockets for biotin guests, binding with an association constant of about 1014 M−1.343 Streptavidin polymers can be assembled by placing the biotin guests in bivalent or tetravalent conformation. Schultz and co-workers used bis-biotin linkers with streptavidin to assemble a building block that is endowed with four linkers per protein: mixing this block with streptavidin allows linear polymerization.344 Streptavidin oligomers of approximately five units are assembled in the first polymerization step, and a second step is used to connect the oligomers into longer polymers consisting of ∼20 units (Figure 36c). This stepwise assembly suggests that a much higher degree of linear polymers might not be feasible with this system. Another example of streptavidin polymerization that uses a biotin guest was published by Ward and co-workers.345 As a guest, the authors developed a preorganized bis-biotinylated terpyridine ligand Biot2-terpy (HG-20), which binds to two sites of streptavidin. A metal ion coordinates two of these linkers, resulting in a tetra-biotin linker. Spontaneous selfassembly of HG-20 with metal ions and streptavidin thus results in a metal-coordinated HG polymer (Figure 36d). 3.3.2.2. Metal Guest/Protein Host Polymers. Protein−metal coordination is a strong, directional supramolecular interaction that occurs through the sharing of lone pair electrons between certain amino acids side chains and the outer orbitals of transition metal ions. Histidine (His), cysteine (Cys), aspartic acid (Asp), and glutamic acid (Glu) can act as donors in this process; the most common natural transition metal ions are Zn(II), Ni(II), and Cu(II). The protein surface can be redesigned to provide sites for metal coordination. This strategy has been used to create discrete oligomeric assemblies

calixarene-based supramolecular polymers using a homoditopic bis(p-sulfonatocalix[5]arene) and a variety of different guest molecules, including porphyrins (HG-11) and viologen dimers (HG-12) (Figure 35a and 35b).330−332 The orthogonality of different cyclic host−guest systems was demonstrated using a combination of calixarene- and cyclodextrin-based monomers (HG-13 and HG-14) and a heteroditopic adamantane− viologen guest (HG-15). These three compounds assemble into linear polymers based on two distinct host−guest interactions (Figure 35c).331 Li and co-workers demonstrated that light can be used to dynamically self-assemble micrometer-long water-soluble supramolecular polymers using α-CD and bis(p-sulfonatocalix[4]arene) (Figure 35d).333 The host in this system was bis(psulfonatocalix[4]arene) (HG-16), and the guest was an α-CDmodified viologen (HG-17). Azobenzene moieties were included in the system to enable light-controlled polymerization by changing the positions of the α-CD in the system and thereby the hydrophobicity. Pillararenes are another class of host molecules that were first reported in 2008 by Nakamoto, Ogoshi, and co-workers.334 Pillararenes are cyclic hosts comprising electron-donating dialkoxybenzene units connected by methylene bridges at the para positions. Two kinds of pillararenespillar[5]arenes and pillar[6]areneseach containing five and six repeating units, respectively, have been synthesized and used to assemble many HG complexes yet mainly in organic media. Yao and coworkers recently reported the first synthesis of a water-soluble pillararene-based system:335 Their AB-type monomer consisted of a long alkyl moiety as the guest and eight trimethylammonium moieties as water-soluble groups. The molecule polymerizes and undergoes a reversible phase transition when heated or cooled. 3.3.2. Protein-Based Host−Guest Systems. Host−guest interactions play a key role in biology and are responsible for many cellular processes, including enzyme−substrate complexation, antigen−antibody recognition, and RNA−ribosome binding. Artificial self-assembling systems that comprise proteins have the potential for not only mimicking naturally occurring protein clusters but also creating functionalized supramolecular polymers. The original character and reactivity of the monomer protein can be exploited to create directional polymers in aqueous environment. Proteins can be conjugated to synthetic or naturally occurring molecules through chemical reactions on certain amino acid side chains or via genetic engineering to include reactive tags or N/C termini that allow for site-selective ligation.336,337 Here, we focus our discussion on supramolecular polymers wherein the protein is part of the host−guest couple. We subdivide protein-based host−guest polymers by the nature of the guest, which may be a small (synthetic) molecule, a metal, or a (small) protein or peptide. We further refer the interested reader to a recent review on the self-assembly of proteins into and onto polymeric architectures,338 a body of work that also includes metal coordination-driven arrays. 3.3.2.1. Small Molecule Guest/Protein Host Polymers. Natural host−guest partners usually achieve their highly specific and strong binding through evolution. Small guest molecules are common drug candidates. In drug development, selection of an effective guest usually follows extensive affinity screening, surrounded by large numbers of competing molecular candidates. This artificial evolution generally results in highly 2443


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Figure 37. (a) Cytochrome b562 (HG-21) and its dimer. Pairwise Zn coordination interactions between neighboring dimers lead to a helical 1D chain. Adapted with permission from ref 347. Copyright 2012 Nature Publishing Group. (b) Addition of an external heme to the cytochrome protein and removal of the natural heme results in the formation of linear polymers, as shown by AFM. Adapted with permission from ref 268. Copyright 2007 American Chemical Society. (c and d) Ni2+-coordinated assembly of linear (HG-23) and cyclic (HG-24) polymers, dependent on the position of the his-tag moieties on the protein surface. Adapted with permission from refs 351 and 352. Copyright 2012 Royal Society of Chemistry and 2013 American Chemical Society. (e) Schematic illustration of Mg2+-induced 1D assembly of HG-25, and TEM micrograph of the supramolecular polymer in 5 mM MgCl2 solution. Adapted with permission from ref 353. Copyright 2009 American Chemical Society.

of cytochrome b562 (HG-21).346 Further rational redesign of this protein enabled the assembly of helical nanotubes and 2D planar structures, depending on the nucleation conditions chosen (Figure 37a).347 Hayashi and co-workers provide another demonstration of cytochrome polymerization.348 A synthetic heme moiety is selectively introduced via a thioether bond onto the protein surface through a single His-Cys mutation (HG-22), and the native heme in the protein is removed; in this case, the externally coupled heme then occupies the heme pocket of a second monomer, thereby producing linear submicrometersized polymers (Figure 37b). The same group subsequently reported on the assembly of a supramolecular myoglobin polymer.349 Myoglobin is an oxygen storage hemoprotein, and as in the cytochrome study, it was provided with an externally attached heme on the protein surface; this was done to drive the formation of the fibrous supramolecular assembly through

successive interprotein interactions between the external heme and the protein matrix. The resulting polymer retains the oxygen storage function of the hemoglobin monomers. A metal-coordination sequence regularly used in protein purification is the 6-His tag, a linear sequence of six histidine residues that can be included in the protein sequence. The histidine side chains form multiple coordination complexes with Ni−NTA surfaces (NTA = nitrilo triacetic acid); affinity constants of 107 M−1 have been reported.350 Using the histidine tag, Liu and co-workers engineered metal-coordinated polymers by genetically fusing the tag to the GST protein (HG-23). This protein forms stable dimers, exhibiting a 2-fold symmetry axis. The engineered N-terminal his-tag is displayed on both sides of the dimer, facilitating linear polymerization into protein nanowires (Figure 37c).351 The system was further engineered to include two chelating sites on both sides of the protein to yield a “V” shape, perpendicular to the C2 axis (HG-24). This 2444


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Figure 38. (a) Schematic representation of the coiled-coil dimers (HG-26). Monomeric subunits can self-assemble to form linear oligomers, cyclic oligomers, or cyclic dimers. Adapted with permission from ref 355. Copyright 2013 American Chemical Society. (b) 1D assemblies containing DsRed-Express and streptavidin/Streptag I fusion assemblies (HG-27), and TEM image of the assembled polymers. Ferritin molecules were used as an internal sizing standard. Adapted with permission from ref 356. Copyright 2009 American Chemical Society. (c) Schematic representation of RNaseS and the ring−chain supramolecular polymerization of RNaseS-based building blocks (HG-28). Adapted with permission from ref 358. Copyright 2010 The Royal Society of Chemistry.

geometry favors the formation of nanorings over linear polymers (Figure 37d).352 The Aida lab reported fuel-driven disassembly of 1D supramolecular polymers, which lead to the intracellular release of encapsulated cargo.353 GroELSP/MC (HG-25), which assembles through coordination with Mg2+ into a hollow tubular 1D structure, functions as a barrel that protects guest molecules against biological degradation. The authors found that fibers containing up to 170 monomer units formed (Figure 37e). Hydrolysis of intracellular ATP into ADP induced conformational changes of the chaperonin units, which in turn generated a mechanical force that led to the disassembly of the linear structure and subsequent release of any captured guests.18 It was shown that not only Mg2+ but also other divalent metal ions such as Ca2+, Mn2+, Co2+, and Zn2+ triggered 1D assembly of the system, while monovalent cations such as Na+, K+, and Cs+ hardly induced self-assembly. Recently, superparamagnetic ironoxide nanoparticles (SNPs) were included as guests in the protein nanotubes, yielding an assembly of micrometer-long one-dimensional arrays of SNPs.354 The SNP nanotubes laterally assembled when placed in a 0.5 T magnetic field and disassembled back to individual 1D nanotubes upon switching off the magnetic field. This is the

premier study reporting lateral assembly of SNP arrays in a magnetic field. 3.3.2.3. Protein or Peptide Guest/Protein Host Polymers. The advantage of using proteins as the linking unit is that they naturally exist in aqueous environment, and thus, no additional chemical modification to ensure water solubility or hydrophobic pocket design is necessary. Despite these advantages, not many synthetic supramolecular systems use entire proteins or protein parts as both host and guest to direct polymerization. However, the following examples show that via the rational design of monomers that use protein host−guest complexes, well-ordered protein arrays can be assembled and studied. Horne and co-workers used helix−helix association to assemble supramolecular polymers; they linked two coiledcoil motifs together via introduced Ser-Cys mutations (HG-26, Figure 38a).355 Three different bridge lengths were chosen, and the monomers were shown to assemble into dimers, cyclic oligomers, and linear polymers with an average chain length of 15−20 units, depending on the bridge and sequence of the protein domain. Bridges used were disulfide bonds between cys residues and bis-bromoacetamide organic linkers to enable thioether ligation. The linker length and rigidity had a significant influence on domain folding and increased coiledcoil affinity led to longer chains. 2445


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Figure 39. Molecular structure (left) and self-assembled nanotubular structure (right) of the cyclic octapeptide (only the peptidic backbone is represented). Adapted with permission from ref 383. Copyright 2013 American Chemical Society.

can be implemented in the design of peptidic supramolecular functional materials, and a wealth of architectures is accessible: cages, spheres, tubes, fiber-like morphologies, tapes, and larger extended sheet-like arrays. The building blocks either can be adapted from biology (e.g., collagens,360 elastins,361,362 ß-sheet systems,363−367 alpha helices/coiled-coils202,368−372) or are obtained using new design strategies based on cyclic, aliphatic and aromatic amphiphiles, or dendritic oligopeptides. We focus our discussion on the latter class of synthetic architectures and highlight several pioneering strategies that have been developed and lead to the successful design of oligopeptide-based onedimensional supramolecular polymers. We provide insight into the supramolecular assembly and polymerization mechanisms and further emphasize the applications and functionalities that are accessible through the use of peptides as building blocks for functional soft matter. Some unique features include stimuliresponsive properties,373 emergence of molecular networks and complexity,374 and biomedical applications in regenerative medicine.38,375 3.4.1. Cyclic Peptides and Peptide Conjugates. Interest is amassing in using oligopeptide building blocks as supramolecular synthons, due to their capacity to selectively form ordered nanostructures. Pioneering work of Ghadiri has led to the design of cyclic oligopeptides with alternating D- and Lamino acids that self-assemble into hydrogen-bonded onedimensional nanotubes in water.376,377 The earliest system was based on the cyclic octapeptide cyclo[-(D-Ala-L-Glu-D-Ala-LGln-)2], where FT-IR and electron diffraction analysis have revealed an antiparallel ß-sheet formation (Figure 39). The backbone amide groups lie nearly perpendicular to the plane of the peptide ring, while the amino acid side chains occupy equatorial positions along the ring’s edge.376,378,379 The authors proposed a cooperative formation of highly stable and long tubes, whereby preorganization of the hydrogen-bonding motif and the multiple supramolecular interactions involved were at the origin for the cooperative nature of the self-assembly mechanism.380 Hydrogen bonding between stack macrocycles had a major contribution in the supramolecular polymerization, since the selective incorporation of N-methylated residues was shown to limit the self-assembly to formation of hydrogen-

Using the matching rotational symmetry between proteins, Noble and co-workers showed that 1D crystallizing strings and 2D binary crystallizing networks can be assembled.356 In particular, when DsRed-Express and Streptavidin/Streptag I are linked by genetic fusion (HG-27), the resulting supramolecular complexes are stabilized extensively by intermolecular interactions (Figure 38b). The self-assembled 1D and 2D materials show crystalline order and were named “crysalins”. The crysalins are assembled through directed interaction between the protomers, which can be homologous or heterologous, depending on the origin of the type of parent chain. Ribonuclease S (RNaseS) is the subtilisin (S) digestion product from ribonuclease A, a pancreatic enzyme. Individually, the corresponding partsnamed S-peptide and S-proteindo not show any enzymatic activity involved in RNA digestion; however, when recombined, the supramolecular complex (Ka ≈ 7 × 106 M−1)357 has an activity comparable to the parental RNaseA. In an attempt to study the supramolecular polymerization mechanism with enzyme-based building blocks, Meijer and co-workers designed AB-type monomeric building blocks by linking the S-peptide to the S-protein via a flexible ethylene glycol linker (HG-28).358 The AB-type monomers were shown to self-assemble into linear and cyclic architectures that were enzymatically active. The polymerization mechanism of these RNaseS-based building blocks confirms that the theory for synthetic ring−chain equilibrium polymerization could be applied to the designed protein-based system (Figure 38c). For many supramolecular protein polymers, the self-assembly and growth mechanisms are poorly understood, which limits precise control over the degree of polymerization and overall assembly. Future progress in this area will lead to the assembly of well-controlled and more complex protein architectures and also provide better insight into understanding protein aggregation phenomena that underlie many diseases. 3.4. Small Peptides and Peptide Amphiphiles

The acquired knowledge of the three-dimensional organization of proteins has been instrumental in engineering functional properties of proteins and in designing new self-assembling systems.359 Since the 1990s the supramolecular chemistry community has demonstrated that rules from natural systems 2446


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Figure 40. Thiol-functionalized GLKLK peptide building block forms a DCL of disulfide-linked macrocycles. (a) Schematic representation of the 6mer macrocycle that nucleates and elongates into supramolecular fibers. Adapted by permission from ref 346. Copyright 2015 Macmillan Publishers. (b) Cryo-TEM image of the fibers. Reprinted with permission from ref 396. Copyright 2010 AAAS.

bonded dimers,381 in agreement with the findings by Lorenzi.382 Ghadiri also prepared cyclic tetrapeptides, composed of alternating α- and 1,4-substituted ε-amino acids, that in organic solvents gave rise to a rarely observed anticooperative polymerization mechanism.384 By incorporating hydrophobic tryptophan and leucine residues in the cyclic octapeptides, the nanotubes were able to partition into the lipid bilayer of vesicles and form transmembrane channels with high ion transport activities.376 A large variety of structural motifs have since been reported for applications not only as ion channels but also as antimicrobial agents and artificial photosynthetic systems.383,385,386 More recently, a series of strategies have been developed to prepare cyclic peptide−polymer conjugates that are able to selfassemble into 1D core−shell tubular morphologies.387−389 Joliffe and Perrier prepared conjugated cyclo[(-L-Trp-D-Leu-LLys(N3)-D-Leu-)2] with water-soluble poly(hydroxyethyl acrylate), poly(acrylic acid), and poly(2-ethyl-2-oxazoline) via triazole linkages. Using a variety of techniques, dynamic light scattering, TEM, and small angle neutron scattering, the aqueous self-assembly into tubes was investigated in great detail.390,391 Most recently, the authors investigated a series of cyclic peptide conjugates with hydrophobic and hydrophilic polyacrylates and -acylamides of controlled molecular weight and low polydispersity, highlighting a clear correlation between the lipophilicity of the polymers expressed as the partition coefficient log P and the proton transport activity of the peptide−polymer conjugates forming trans-bilayer channels.392 The assay was based on calcein and carboxyfluorescein entrapped in large unilamellar vesicles (LUVs), which enabled the authors to conclude that proton transfer occurs through unimeric nanotube channels, rather than “clustered” barrels stave or carpet-like bilayer disruption. Experiments with thermoresponsive poly(N-isopropylacrylamide) conjugates lead to temperature-induced channel formation and allow for thermal gating of proton efflux properties. The same authors reported the formation of unique Janus-type morphologies, obtained via phase separation or demixing of poly(butyl acrylate) and poly(styrene) in the corona of the peptide− polymer conjugates. These self-assembled nanotubes also partition in phospholipid bilayers but form dye-leaking

macropores via phase segregation due to the incompatibility of poly(styrene) and phospholipids.393 The Otto lab has recently disclosed a series of reports on selfsynthesizing macrocyclic molecules in water. The strategy was based on reversible dynamic covalent chemistry using dithiol building blocks. Under oxidative conditions the dithiols form an equilibrating mixture of disulfide-linked macrocycles, referred to as dynamic combinatorial library (DCL).77,394,395 Usually the distribution of the library members in DCLs can be shifted by the external addition of template molecules, which amplifies the formation of members with a high affinity to the template at the expense of weaker binders. Otto and colleagues now show that the library distribution can be shifted if one of the macrocycles is able to recognize itself through self-assembly of β-sheetencoded GLKLK peptide side chains (Figure 40).396 This induced shift of the library composition toward the selfassembling macrocycle gives rise to a self-replicating material.397 Smaller macrocycles (3mers and 4mers), which are unable to self-assemble, are consumed at the expense of larger ones (6mers and 7mers). Supramolecular polymerization of the disulfide-linked β-sheet-functionalized peptides into large micrometer long fibers was observed in cryo-TEM and further characterized through CD, FTIR, UV, and fluorescence spectroscopy. Monitoring of the library composition via HPLC-MS enabled the authors to establish growth profiles for the individual macrocycles. In combination with seeding experiments these confirmed that the self-assembling hexa- and heptameric macrocycles are formed through exponential growth, a hallmark for self-replicating systems. Ashkenasy earlier reported linear amphiphilic peptides with up to 12 amino acids, including a −(FE)n− repeat domain, that form soluble 1D β-sheet aggregates in water.398 These were able to act as templates for self-replication using native chemical ligation of an electrophile thioester and a nucleophilic Nterminal cysteine. A clear signature of template-assisted autocatalytic production of the β-sheet forming peptide was observed, and kinetic analysis revealed exponential growth. Sonication and disassembly of the template aggregates were found to increase the rate of product formation. Due to the fact that the monomeric form of the template is unable to adopt a stable secondary structure in solution, the β-sheet-directed nanostructures serve as the nuclei for autocatalysis.399 Detailed 2447


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ization of these peptide amphiphiles into very long 1D nanorods and -fibers in aqueous buffer.404,405 The general design of the building block combines an aliphatic hydrocarbon chain (domain I) with a peptide block that contains a hydrophobic sheet-forming sequence (domain II), 1−3 water solubilizing charged amino acids (domain III), and a bioactive signaling epitope (domain IV) (Figure 41). The morphology of the nanofibers has usually been determined using cryogenic and dry TEM, but the internal structure was characterized using

kinetic analysis have revealed that a decay in the catalysis is observed due to β-sheet aggregation, which can proceed past the small monofibrils to form bundles and finally larger tubelike aggregates, which are catalytically inactive.399 In a recent study Otto and coauthors confirm that the hydrophobicity of the peptide building block, in combination with multivalent effects, determines which of several potential self-replicating materials emerges from a DCL.400 A variety of peptides of the type Gly-Leu-Lys-X-Lys (where X = 1-Nal, Cha, p-Cl-Phe, Phe, Leu, Ala, Ser) were attached to aromatic dithiol building blocks, and clear trends were observed. As the hydrophobicity of the building block decreased, the size of the emerging self-replicating macrocycle increased, meaning that larger macrocycles carrying more peptides needed to be formed in order for the self-assembly into supramolecular fibers to become energetically favorable (e.g., 6mer for X = Phe and 8mer for X = Ala). In the case of the most hydrophobic derivatives (X = 1-Nal, Cha, p-Cl-Phe), smaller macrocycles 3mers, 4mers, and 5mers self-assemble and autocatalysis was not observed, which led the authors to conclude that selfreplication only occurs if the population of the replicator in the library is small and its spontaneous formation is inefficient relative to the autocatalytic formation. The results also highlight that in the case of the larger macrocycles (≥6mers), which are unstable compared to the 3mers and 4mers in the absence of a supramolecular polymerization process, mechanical agitation is critical in overcoming the kinetic barrier for the formation of these species. The authors concluded that by shear stressinduced (shaking or stirring) mechanical fragmentation of the fibers the formation of fiber ends promotes the growth of replicator. These features were further utilized to produce supramolecular polymers of controllable length, low polydispersity, as well as blocked morphologies.401 By subjecting the fibers to high shear stress in a Couette cell, breakage of fibers into shorter species was achieved. For example, at a shear rate of 67 405 s−1 fibers with a number-average length distribution Ln = 60 nm with a narrow polydispersity index of 1.04 were obtained. These seeds were then used to mediate fiber growth using a solution of cyclic 3mers and 4mers, which are kinetically trapped in the nonassembling state. Using the reversible character of the disulfide covalent chemistry, more of the assembling molecules are produced as the growth proceeds into well-defined materials: the fiber length correlates linearly with the amount of 3mer/4mer (monomer reservoir) added, and very low polydispersity indices in the range of 1.04−1.07 are obtained. The living property of the fiber ends of the system also enabled one to adjust the type of monomer added to a solution of seeds and thus to prepare supramolecular triblock copolymers. Finally, UV photoirradition402 could also be used to stabilize the fibers via intrafiber disulfide cross-linking, which enhances fiber stability. The Otto lab has thereby elegantly shown that the combination of reversible covalent bonds and noncovalent interactions is well suited for kinetically controlled product formation in self-assembly rather than structures that are in thermodynamic equilibrium,27,403 and exciting opportunities arise in complex molecular networks and supramolecular selfsynthesizing materials. 3.4.2. Aliphatic Peptide Amphiphiles. A widely applicable and important set of building blocks for the design of selfassembled and functional soft matter in water is based on amphiphilic fatty acid conjugated oligopeptides.38 Seminal work by the Stupp lab demonstrated the supramolecular polymer-

Figure 41. (a) Chemical structure and space-filling model of the peptide amphiphile palmitoyl-V3A3K3-RGDS-NH2, highlighting the four structural domains (I−IV), and a schematic representation of the self-assembly into a nanofiber, with red spheres representing water molecules.38 Adapted with permission from ref 360. Copyright 2011 Elsevier. (b) Cryo-TEM micrograph of the peptide amphiphile palmitoyl-V2A2E2-NH2 in water, revealing high aspect ratio nanofibers with diameters of about 7 nm. Reprinted by permission from ref 409. Copyright 2014 Macmillan Publishers Ltd. 2448


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(OEG)4) led to self-assembly into nanofibers at pH 7.5, while the functionalization on to the C-terminus ((OEG)4-H6-KC12) led to spherical micelles at the same pH. By inverting the functionalization strategy a completely different morphology was thereby obtained; it was hypothesized to result from the increased bulkiness between the β-sheet region and the hydrophobic tail due to the formation of a kink on the Cterminus, caused by the additional primary amide of (OEG)4H6-KC12. This prevents the formation of ordered β-sheet 1D assemblies. Upon protonation of the histidine residues by adjusting the pH to 6, nanostructures, micelles, and fibers disassemble. Intriguingly, the nanofibers based on C16-H6(OEG)4 showed a greater capacity in the encapsulation of the chemotherapeutic drug camptothecin and furthermore led to higher tumor accumulation in vivo compared to the micelles obtained from (OEG)4-H6-KC12. The group of Goldberger reported the fine tuning of the pH transition in switchable amphiphiles−micelle−nanofiber morphologies.419 The building block consisted of palmitoyl-XA3E4NH2; the XA3 block is a known β-sheet-forming domain (where X is any amino acid with a hydrophobic side chain), and the four glutamic acids linked on the C-terminus guarantee water solubility. Due to the Coulomb repulsion of the deprotonated glutamic acid at neutral pH, these amphiphiles are molecularly dissolved at low concentrations. By lowering the pH value the self-assembly into nanofibers is induced, driven by the formation of intermolecular β-sheets and attractive forces in the hydrophobic block, aided by desolvation. The balance of these attractive and repulsive interactions420 can be manipulated by adjusting the hydrophobic amino acid X in the β-sheetforming region. If the β-sheet propensity of the amphiphiles is enhanced by increasing the hydrophobic character of the amino acid following the trend I > F > V > Y, the pH transition is gradually raised from pH 6.0 to pH 6.6. The apparent pKa of the acidic side groups in the amphiphile is therefore shifted driven by the self-assembly and does not correlate with the actual pKa of an isolated glutamic acid in water (4.7−4.9). The self-assembly mechanism was recently investigated in more detail using multiscale molecular dynamics simulations by the groups of Nguyen and Shen.421 The interplay between attractive and repulsive intermolecular interactions that we have described so far have been employed in an elegant strategy by the Hartgerink research lab in order to produce objects of finite size instead of “infinitely” long fibers (micrometer length scale) that are usually obtained for amphiphilic peptide.422 A library of nine peptides was prepared with a triblock A-B-A oligopeptide design. The A blocks were oligolysines of varying length, and the middle B block consisted of an alternating glutamine-leucine repeat unit which is encoded to form β-sheets (Figure 42). Supramolecular polymerization was observed in buffer of controlled pH and ionic strength using TEM, cryo-TEM, IR, and CD spectroscopy. The concept of molecular frustration was introduced as a means to hamper the attractive forces from the middle block with repulsive electrostatic forces from the charged oligolysines in the periphery to yield in the case of K2(QL)6K2 finitely sized nanofibers with a length of 150 ± 45 nm. By increasing the pH or the ionic strength, repulsive forces were screened, the polymerization became increasingly favorable, and the length of the fibers increased accordingly. Since the first report in 2001, the Stupp research group has disclosed a number of reports on peptide amphiphiles as promising materials for biomedical applications:38 self-

transmission infrared (IR) spectroscopy and polarization modulation-infrared reflection−absorption spectroscopy (PMIRRAS): the ß-sheet is oriented parallel to the long axis of the nanofiber. The internal order is highly dependent on peptide sequence and morphology,406,407 also supported by CD investigations.408 Molecular dynamics simulations using a coarse-grained model were performed by the group of De la Cruz and have shown that the self-assembly is governed by an intricate balance between desolvation and vdW interactions in the hydrophobic alkyl tails with a network of hydrogen bonding between the peptide segments. This leads to the formation of different morphologies, single and stacked parallel β-sheets, spherical micelles, micelles with β-sheets in the corona, and long cylindrical fibers. The equilibrium between those is suggested to be governed by the presence of nucleation seeds.69 Schatz reported atomistic molecular dynamics simulations including explicit water with physiological ion concentration and confirmed that based on the investigated palmitoylSLSLAAAEIKVAV-OH amphiphiles, cylindrical configurations are most stable, resulting in nanofiber formation.70 A broad distribution of secondary order was found in the converged structures, with the highest β-sheet content in the SLSL and IKV domains, and critically for biomedical applications (vide infra), the binding epitope sequence IKVAV is exposed on the surface of the fibers. Even though detailed experimental mechanistic studies that unravel the full details in the supramolecular polymerization have not been reported, it was proposed that the self-assembly process occurs via a cooperative growth mechanism, in analogy to folding of β-sheet peptide strands.3 Most recently a collaboration between the Meijer and Stupp laboratories has explored kinetic investigations into the self-assembly of palmitoyl-V3A3E3-NH2 amphiphiles and highlighted the impact of the assembly pathway on the produced supramolecular morphology.66 The addition of water as “bad” solvent to hexafluoroisopropanol (HFIP) as “good” solvent was shown to induce the self-assembly of molecularly dissolved species into polymeric species. Extensive steady-state and kinetic experiments were carried out in order to investigate the self-assembly as a function of the solvent composition: at the critical solvent composition of 15% HFIP, which induces the formation of ordered morphologies, the assembly rate is the slowest, in analogy to some reported examples for protein folding. Importantly, in this narrow solvent composition regime, the formed morphologies also have high kinetic stability and do not readily fall apart, which leads to hysteresis effects. This study exemplifies that insights into the characteristic dynamics of noncovalent systems are key in providing efficient and optimum assembly pathways for functional supramolecular materials in water. Alkyl-substituted peptide amphiphiles are excellent building blocks for the development of stimuli-responsive materials: pH and ionic strength triggered self-assembly events are based on charged, basic, or acidic amino acid side chain functionalities. In the recent literature several systems have been reported.410−414 We restrict our discussion to a few examples and refer the interested reader to recent reviews.38,415,416 The Stupp lab has disclosed a report on self-assembling peptide amphiphiles, whereby the shape of the pH-responsive nanostructures can be controlled via molecular design.418 The amphiphiles were based on a hexahistidine (H6) β-sheet domain functionalized with a solubilizing oligo(ethylene glycol) chain and a hydrophobic tail. Attaching a hydrophobic chain on the N-terminus (C16-H62449


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example, in optoelectronic and piezoelectric devices, sensors, or superhydrophobic surfaces.436−440 Micrometer-long fibers tend to entangle at higher concentrations to form physical networks and strong self-supporting hydrogels, which are a promising platform for self-assembled gels for applications in tissue engineering and regeneration.441,202,442 Peptide-based low molecular weight gelators (LMWG) are an extensively investigated field,443−446 where the formation of hydrogels is generally governed by a balance of attractive and repulsive forces, similar to the self-assembly of aliphatic peptide amphiphiles described above. Herein, we focus our discussion on the manipulation of intermolecular forces, thermodynamic and kinetic aspects of the supramolecular polymerization mechanisms that dictate one-dimensional self-assembly of gelating molecules, using pH or enzyme catalysis as external stimuli.447−450 For a more detailed picture on hydrogel formation and their physical characterization, we refer the interested reader to the recent literature of peptide-based supramolecular hydrogels.88,451−453 One prominent class of LMWGs consists of short di- or tripeptide units linked to large aromatic groups like fluorenylmethoxycarbonyl (Fmoc) or naphthalene derivatives.454−462 Generally, self-assembly is triggered by reducing the pH and by protonating the C-terminal carboxylic acid, which decreases the hydrophilicity and water solubility of the peptide.88,463 The critical pH value for these peptide LMWG is strongly dependent on their apparent pKa and therefore the overall hydrophobicity of the molecule: hydrophobic shielding enhances the thermodynamic driving force for the aggregation process and leads to stronger shifts in the apparent pKa values. The Adams research group exploited this concept in designing hydrogelator molecules with pH-controlled self-sorting properties464 in the gelation process (Figure 43):465 the two building blocks exhibit different apparent pKa values in water due to their dissimilar hydrophobicity. If the pH of an aqueous solution containing both gelator molecules was lowered gradually via the hydrolysis of gluconic acid δ-lactone,466 the pKa of the first molecule is reached at pH 5.9 and induces its self-assembly, while the second molecule does not undergo aggregation until pH 5.1. The order of the assembly is therefore predefined by the pKa of the gelator molecules. This tool allows external manipulation of the hydrogel composition via pHcontrolled sequential self-assembly. The programmable supramolecular aggregation has previously been combined with the electrochemical oxidation of hydroquinone in order to create pH gradients on the surface of electrodes.467 The Walther group recently reported a concept to program the time domain of pH-switchable supramolecular aggregates.468 The strategy was applied to a large number of examples in the self-assembly of block copolymer-based micelles and vesicles, Au-nanoparticle-based clusters, and antiparallel-directed β-sheet fibrils. The assemblies are unstable in low pH due to Coulomb repulsion of charged functional side chains and are stable at high pH after deprotonation/ protonation events of the acidic/basic groups. By injecting a solution of a lactone (referred to as dormant deactivator) and a base (promoter) to an acidic solution of unstable assemblies, the alkaline pH jump promotes supramolecular aggregation into a transiently stable state at high pH. Under these conditions the dormant deactivator hydrolyses, leading to the formation of a carboxylic acid which in turn decreases the pH. The rate of hydrolysis and therefore pH decay kinetics is rapid for gluconic acid δ-lactone (time scale of minutes), slower for

Figure 42. (a) Chemical structure of the Kx(QL)yKx series of peptides (x = 0−4, y = 2−6), and the proposed model of nanofiber formation, indicating the hydrophobic packing region (in blue), the axis of hydrogen bonding, and the repulsive positive charges (in red). (b) Cryo-TEM micrograph of the peptide K2(QL)6K2 in 10 mM Tris buffer at pH 7.4 with 150 mM NaCl. Adapted with permission from ref 422. Copyright 2007 American Chemical Society.

assembled nanofibers can yield scaffold materials that support cells and, if derivatized with bioactive ligands or epitopes, can signal cells for differentiation.423 In vivo studies have revealed the potential of bioactive supports in spinal cord injury,424 the formation of blood vessels,425 and regeneration of bone426,427 and cartilage.428 β-Sheet oligopeptide-directed nanofibers have also been reported as efficient scaffolds for RNA and DNA complexation and gene transfer.132,429−435 Following the discussed strategies in the self-assembly of functional supramolecular polymers, the community has grown quickly in realizing that molecular self-assembly is a viable nanotechnological route to create supramolecular biomaterials via a bottom-up approach. 3.4.3. Aromatic Oligopeptides and Peptide Conjugates. Seminal work by the Gazit lab was based on small aromatic building blocks, diphenylalanine (FF), which selfassembles into extremely stable, stiff, and micrometer-long rodand tube-like morphologies, with potential applications, for 2450


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Figure 43. (a) Chemical structures of both gelator molecules. (b) Time-dependent hydrolysis of glucono-δ-lactone to gluconic acid. (c) Kinetics of hydrolysis. If two molecules have different pKa values, a slow decrease in pH will lead to the pKa of one molecule being reached first (blue cross). Assembly occurs before the pKa of the second molecule (red cross) is reached. This leads to sequential self-assembly. (d) Schematic representation of the sequential self-assembly process. Adapted with permission from ref 465. Copyright 2013 Macmillan Publishers Ltd.

Figure 44. (a) Biocatalytic self-assembly of Fmoc-dipeptide methyl esters (with T, F, L, V amino acids and a subtilisin cleavable methoxy group) into nanofibers, shown by AFM analysis of the initial stages of the process. (b) Enzyme-driven DCL using thermolysin and a mixture of Fmoc-T-OH, H2N-F-OMe, and H2N-L-OMe generating a distribution of Fmoc-TF-OMe (green) and Fmoc-TL-OMe (black) (solid lines, closed symbols). Dashed line and open symbols represent the time course experiment after sequential addition of Fmoc-T-OH, H2N-L-OMe, thermolysin, and after 5 days the competitor H2N-F-OMe resulting in near complete replacement of Fmoc-TL-OMe with Fmoc-TF-OMe driven by thermodynamically controlled self-assembly into the most stable nanofibers; (inset) schematic representation of the relative free energy landscape. Reprinted with permission from ref 447. Copyright 2009 Macmillan Publishers Ltd.

methyl formate (hours), and slowest for ε-caprolactone (days). The authors refer to this simple and elegant concept as a selfregulated closed system that produces kinetically controlled transient self-assembled states with tunable time domains over 4 orders of magnitude.

The self-assembly into supramolecular peptide nanofibers and hydrogels employing biocatalytic strategies has been reported using phosphatase/kinase469 systems by Xu450,459,470 and Stupp471 or using proteases by Ulijn (Figure 44).447,448,456 The Ulijn group was able to show that in water the nonspecific endoprotease thermolysin can be used to catalyze the synthesis 2451


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of peptides if supramolecular self-assembly provides a driving force that shifts the thermodynamic equilibrium for the peptide bond formation in favor over hydrolysis.448 Using a DCL approach, Ulijn and colleagues more recently performed competition experiments with Fmoc-X-OH as electrophile (X = G, F, T) and nucleophilic H2N-Y-OR (Y = G, F, L, T; R = Me, H) with thermolysin as catalyst. Using CD, FTIR, and photoluminescence spectroscopy, HPLC analysis of the library composition, and TEM and AFM of the aggregate morphologies, the authors showed that the enzyme-assisted self-assembly is fully reversible and that the equilibrium is driven by the formation of antiparallel β-sheet and π-stackdirected nanofibers, whereby the most thermodynamically stable components are favored (Figure 44).447 The powerful combination of supramolecular interactions and reversible enzyme-catalyzed covalent chemistry was exploited by Ulijn in the formation of peptide nanofibers that display dynamic instabilities (vide supra).472 In order to meet the key criteria for such nonequilibrium systems, the protease α-chymotrypsin was used to catalyze the transacylation for the forward reaction between an acyl donor Nap-Y-OMe and three hydrophobic amino acids H2N-X-NH2 (functionalized as amides, where Nap = naphthoxyacetyl and X = F, Y, L) to form the dipeptides Nap-YX-NH2. In the case of Nap-YY-NH2, HLPC analysis was used to show that the kinetically driven transacylation is almost instantaneous (∼1 min), and hydrogelation was observed due to fiber formation of Nap-YY-NH2. Critically, the stability of the hydrogel was only temporary, and the authors were able to show that the formed micrometer-long supramolecular nanofibers become shorter over time, due to competing hydrolysis of the dipeptide, and finally micelles are obtained, resulting in a free-flowing solution. Since the thermodynamically driven enzyme-catalyzed hydrolysis into Nap-Y−OH and H2N−Y−NH2 is pH dependent, the lifetime of the transient hydrogel is higher at pH 8 (36 h) and lower at pH 10 (8 h). The lifetime of the hydrogel could also be tuned by adjusting the concentration of the catalyst α-chymotrypsin. Furthermore, the temporary hydrogelation could be repeated over three cycles via the addition of acyl donor Nap-Y-OMe as chemical fuel. Most recently, the Ulijn group reported transient nanofibers, based on α-chymotrypsin-catalyzed transacylation/ hydrolysis of tripeptides of the type H2N-DFX-NH2, using H2N-DF-OMe as acyl donor and nucleophilic H2N-X-NH2 (X = F, Y, W, L, V, S, T).473 Only in the case of X = F or Y, temporary peptide formation, self-assembly, and hydrogelation were observed, followed by hydrolysis into H2N-DF-OH and H2N-X-NH2. The lifetimes of the gels based on H2N-DFF-NH2 are significantly higher (24 h) compared to H2N-DFY-NH2 (4 h). In direct competition experiment, however, the enzymecatalyzed formation of H2N-DFY-NH2 is preferred over H2NDFF-NH2 with selectivity values of 7:3 after 1 h of reaction, suggesting that the kinetically preferred nanostructure is formed rather than the thermodynamically most stable one. Sequencedependent pathway selection in the biocatalytic self-assembly was thereby demonstrated, and the dynamically unstable assemblies could be refueled several times by addition of H2N-DF-OMe. The process of chemical fueling (see above) in synthetic nonequilibrium supramolecular systems was introduced for the first time by the group of van Esch and co-workers (Figure 45).164 Dibenzoyl-L-cysteine forms hydrogels through entanglement of elongated supramolecular fibers when intermolecular Coulomb repulsion of the dicarboxylate is screened, for

Figure 45. Reaction cycle of the van Esch dissipative self-assembly system. The dicarboxylate building block can react with MeI (fuel) to give monoester MeO-DBC-O− and diester MeO-DBC-OMe (in red). The latter can self-assemble into gelating fibers. In the assembled state the “activated building block” can dissipate its energy through hydrolysis and revert to its monomeric state (in blue).164 Adapted with permission from ref 346. Copyright 2015 Macmillan Publishers Ltd.

example, via lowering of the pH. The authors use methyl iodide as chemical fuel for the formation of dimethyl ester, which was shown to lead to fiber formation and hydrogelation. When the fuel is consumed the gel falls apart due to hydrolysis of the diester, which at a constant alkaline pH forms the dicarboxylate to return to a nonaggregated state, the thermodynamic minimum of the system. The energy provided by the fuel thereby keeps the supramolecular system in an outof-equilibrium situation, which without the addition of new fuel is able to dissipate energy via hydrolysis of the diester. HPLCMS, light scattering, SEM analysis, and monitoring of the hydroxide ion consumption during hydrolysis were used to show that the system could be cycled between the two states via repeated addition of fuel. It is expected that out-of-equilibrium self-assembly and the development of synthetic dissipative systems are an important step forward in understanding structural adaption in biological systems and will open up new opportunities to create supramolecular systems with elaborate structural features and functional diversity. In the discussion of applications for peptide-based supramolecular polymers in water, we have so far focused the largest part of the examples on biomedical technologies, regenerative medicine, stimuli-responsive materials for the controlled release of cargo, and synthetic ion channels. In a small extension to supramolecular polymerization of π-conjugated molecules (cf. section 3.2) we also highlight a selected number of examples on the self-assembly of hybrid π-conjugated-peptide materials in aqueous environments. Since the performance of organic semiconductors is strongly dependent on supramolecular packing, the conjugation of peptides with oligomeric semiconductors is a strategy targeted by a number of research groups in order to prepare hierarchically ordered materials with tunable optoelectronic properties.297,298,474 For example, the groups of Klok, Bäuerle, Stupp, Börner, and Tovar have reported examples for peptide-oligothiophene conjugates.475−480 Alternatively, Holmes prepared peptidic α-helices conjugated to sexithiophene in the side chains and investigated their optoelectronic properties in organic gels.481 Frauenrath 2452


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and coauthors reported the preparation of ordered microfibers from perylene diimide, oligothiophene, and diacetylene-peptide conjugates, albeit not in water.482,483 A number of studies have been disclosed on linear and dendronized amphiphilic peptides conjugated to naphthalene and perylene diimides, oligothiophenes, and oligophenylenevinylenes as well as their selfassembly into micrometer-long fibers, hydrogels, and their photophysical properties.476,484−494 For example, the groups of De Feyter, Meijer, and Schenning prepared hydrophobic tri(pphenylenevinylene) coupled to oligopeptide blocks. Using scanning tunneling microscopy (STM) their two-dimensional self-assembly demonstrated the formation of bilayers via antiparallel β-sheet conformation. Aggregation was observed in organic solvents as well as in water. Cryo-TEM, AFM, light scattering, and optical studies revealed that in water selfassembled helical nanofibers are produced.495 In a recent report, Tovar and co-workers demonstrated electronic function within two-component peptide ensembles.485 DFAA-flanked 1,4-distyrylbenzene (OPV3) HODFAA-OPV3-AAFD-OH and quaterthiophene (4T) HODFAA-4T-AAFD-OH (Figure 46) provided full water solubility and pH-responsive self-assembly. At alkaline pH 10, the negatively charged bioorganic hybrids are molecularly dissolved; they formed ordered 1D nanofibrillar aggregates by acidifying the solution to pH 2. Using CD, UV−vis, steadystate, and transient photoluminescence spectroscopies the order in the coassembled aggregates was investigated. Energy transport from the donor (OPV3) to the acceptor sites (4T) was demonstrated, involving multiple mechanisms such as exciton migration and resonance energy transfer, which was also dependent on whether the two-component π-conjugated nanostructures were thermally annealed. This strategy holds great promise for the development of bioelectronics materials, artificial photonic antennae, and photosynthetic unit mimics. Another highly promising strategy for bioimaging and diagnostic applications is the development of supramolecular bioinorganic optoelectronic materials, for example, luminescent Pt(II) complexes496,497 or Au(I)−metalloamphiphiles.498,499 3.4.4. Dendritic Oligopeptide Amphiphiles. Seminal work by Percec and co-workers led to the design of dipeptides equipped with dendritic side chains.500 These dendronized dipeptides were reported to self-assemble into helical porous columnar aggregates in bulk, in solution, and in vesicles. The initial design was based on L- and D-amino acid-based BocTyr(OR)-Ala-OMe, with R being a nonpolar 3,4-disubsituted benzyl ether-based Fréchet-type dendritic wedge. A combination of NMR, CD, and UV−vis spectroscopy, X-ray diffraction, and TEM analyses showed that in cyclohexane solutions and in the solid state, cooperative self-assembly occurs to form helical supramolecular polymers with a columnar morphology stabilized via intermolecular hydrogen bonding.501 In a series of detailed reports the role of the stereochemistry of the dipeptide,501,502 the choice of protecting group,503 and the length of the terminal alkyl groups on the dendritic side chains504 were investigated and the consequences for the internal structure of the helical arrangements as well as the stability of the pores. The hydrophobic nature of the dendritic wedges did not allow the supramolecular polymerization to be carried out in pure water as such, but instead, the helical aggregates could be embedded in phospholipid bilayer membranes of liposomes. Using encapsulated pH-sensitive dye assays, the selectivity for H+ translocation across the membranes was demonstrated, similar to natural proton-

Figure 46. (a) Molecular structures of the DFAA-based OPV3 and 4T π-conjugated peptide building blocks and their coassembly into heterostructured 1D stacks shown as space-filling model, illustrating the possible energy transfer processes (resonance energy transfer (RET) and carrier migration). (b) Stained TEM images of the nanofibers (1 mol % 4T) with a width of 5.6 ± 0.64 nm. Adapted with permission from ref 485. Copyright 2015 The Royal Society of Chemistry.

permeable gramicidin channels.500 More recently, the Percec lab succeeded in stabilizing the helical pores based on selfassembled Boc-Tyr(OR)-Ala-OMe by replacing the peripheral benzyl groups in the dendrons with larger naphthyl groups.505 In the solid state this led to columnar aggregates with a diameter (Dcol) that increased from 71.3 to 82.3 Å and an enlarged pore diameter (Dpore) from 12.8 ± 1.2 to 14.5 ± 1.5 Å. In cyclohexane solutions the thermal stability increased from Tm = 295 K to Tm = 313 K. Intriguingly, by assembling the pores in phospholipid vesicles, the larger pore size enabled not only the transport of protons but also water molecules, as shown via a combination of pH-sensitive dye assays and 2453


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osmotic pressure-driven changes in size of giant unilamellar vesicles (GUVs). Selectivity over potassium and sodium cations was maintained, which demonstrates the controlled design of functional supramolecular dendrimer assemblies, with applications as nonbiological porous architectures. The group of Lee has utilized a range of amphiphilic peptide architectures, linear,506 rod−coil blocks,507 T-shaped,508 cyclic,509,510 and dendritic structures,511,512 that self-assemble into toroids or nanorings, vesicles, sheets, or rod-like filaments. For example, the Tat cell-penetrating peptide was functionalized with dendronized nonpolar tails ranging from 2 to 8 lipid tails using lysine as a branching agent.511 In this particular case the cationic nature of the peptide itself does not code for selfassembly, but we point out that depending on the length of the nonpolar chain and the degree of branching, spherical micelles, short and long cylindrical micelles were obtained. The crucial impact of hydrophobic packing was further observed in the stability of the assemblies, the loading capacity with Nile red as hydrophobic dye, and their critical aggregation concentration, which was improved from 208 to 21 μM using the generation 2 stearic acid based dendron, compared to the generation 1 dendron. Using Hartgerink’s molecular frustration concept, the Besenius lab has recently disclosed dendritic peptide amphiphiles (using a C3-symmetrical scaffold)513−519 that selfassemble into 1D supramolecular polymers of controlled length. Dendritic nonaphenylalanines were functionalized with carboxylic acid Newkome-type dendrons on the C-terminus, which enabled the repulsive electrostatic contribution in the frustrated growth to be screened by adjusting the pH and ionic strength of the buffered environment.520 This multistimuli responsive behavior in the supramolecular polymerization was analyzed using state diagrams, analogous to self-assembled natural spherical or filamentous viruses. By fluorination of the aromatic amino acids, the monomer to polymer transition can be shifted from pH 5.0 and 7.4 at physiological ionic strength.521 These findings are in full agreement with reports from the Goldberger and Adams laboratories (vide supra). By increasing the hydrophobic character of the oligopeptide, the apparent pKa of the terminal acid groups is shifted to higher pH values compared to nonfluorinated peptidic building blocks, driven by the increased thermodynamic driving force of the self-assembly. This effect further highlights the crucial impact of hydrophobic shielding in supramolecular polymerization processes in water.522 In this section we have so far described Coulomb forces as a repulsive contribution in aqueous self-assembly processes. By installing opposite charges into the complementary monomeric building blocks, molecular recognition events can be stabilized, as elegantly shown for self-assembly processes of peptide amphiphiles by Stupp408,523,524 or the self-assembly of β-barrels by the Matile group.525−527 In 2000 Woolfson and colleagues reported the supramolecular polymerization of peptide sequences using a leucine zipper motif, which is based on the formation of dimeric α-helical coiled coils.528 Their design relied on the formation of heterodimeric coiled coils confirmed by CD spectroscopy and X-ray diffractionwith overhanging ends of opposing net charge. The latter were suggested to nucleate a quasi-2D supramolecular polymerization to yield fiber-like structures that further coagulate into bundles, as observed by TEM (Figure 47). More recent molecular designs included engineering of the morphology of the fibers, for example, by coassembling T-shaped with linear

Figure 47. (a) Design principles of the self-assembling-fiber (SAF) peptides: complementary charges in companion peptides direct the formation of staggered, parallel, and codirectional heterodimers, and the resulting “sticky ends” are also complementary and promote longitudinal association into extended fibers. (b) Complementary charged pairs on the outer surfaces of the coiled-coil protofibrils promote protofibril−protofibril interactions, fiber assembly, and thickening. (c) TEM micrographs of negative stained third-generation fibers; scale bars 50 nm (left) and 2 μm (right inset). Adapted with permission from ref 533. Copyright 2007 National Academy of Sciences, U.S.A.

peptide sequences to produce branched fibers.529−531 Furthermore, the stability of the fibers could be tuned to physiological ionic strength, to higher temperatures, and to a lower critical aggregation concentration.532 The latter are very important parameters when targeting biomedical applications. The thickened fibers and their stabilization and highly ordered structure was established from detailed TEM and WAXS experiments (Figure 47).533 More recently, Hartgerink and coworkers developed a different strategy for polymerization of αhelical coiled-coil oligopeptides but without charged end groups;534 in their design the aggregation is not driven by 2454


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Figure 48. Representation of the pH-switchable supramolecular copolymerization of the anionic/cationic β-sheet-encoded dendritic peptide amphiphiles. (a) Tunable pH-stability window for the supramolecular copolymers is related to the peptide sequence. Adapted with permission from ref 417. Copyright 2013 John Wiley and Sons. (b) Selectivity in supramolecular homo- and copolymerization is regulated via the pH of the phosphate buffer; stained TEM micrographs show supramolecular nanorod morphologies for the copolymers with a number-average length distribution of 56 nm (scale bar is 100 nm and in the inset 10 nm).535 Adapted with permission from ref 535. Copyright 2015 John Wiley and Sons.

ylate or ammonium functional groups in the side chains of the comonomers, disassembly of the polymers occurs in a sharp response to the change at pH 3.6 and 8.9. Experimental characterization of the materials included CD spectroscopy, 13C CP-MAS NMR, TEM, as well as multiscale molecular modeling. The affinity of the comonomers was increased by incorporating a more hydrophobic leucine amino acid into the peptide strands, which allowed fine tuning of the pH trigger, and the stability window for the copolymers was increased from pH 3.6−8.9 for the alanine-based structures to pH 2.0−12.0 for the leucine equivalents. The latest development made use of phenylalanine alternated with charged amino acid groups in either of the comonomers, which were further equipped with minimalistic FRET pairs.535 The increased hydrophobicity led to a previously unobserved pH-triggered copolymer to homopolymer transition, while the oppositely charged comonomer is released during the transition. In addition to TEM and CD spectroscopy, photoluminescence was used to show that the system can be switched reversibly between the homopolymer of glutamic acid-based monomer in acidic pH,

attractive Coulomb interactions but by vdW forces and desolvation effects. The supramolecular polymerization of the peptides described by Woolfson and Hartgerink is cooperative in nature, which was suggested to result from a combination of the hydrophobic effect and allosteric effects, due to the preorganization of the oligopeptide into α-helical coiled coils prior to supramolecular polymerization.3 The Besenius lab recently demonstrated a strategy for 1D supramolecular polymerization by using a set of two complementary dendritic supramolecular comonomers (Figure 48).417,535 These were based on β-sheet-encoded pentapeptides using an alternating sequence of hydrophobic and hydrophilic amino acids. The incorporation of glutamic acid and lysine along with alanine residues into the peptide sequence of either of the building blocks leads to oppositely charged comonomers at a neutral pH. The hierarchical supramolecular copolymerization into nanorods is thereby stabilized by the formation of parallel β-sheet-encoded hydrogen bonds, Coulomb attractive interactions, and hydrophobic shielding. If these charges are screened by either protonating or deprotonating the carbox2455


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oligonucleotides will likely further decrease, and longer chains will become increasingly accessible. While Watson−Crick hydrogen bonds facilitate predictable and sequence-specific hybridization of DNA molecules (Figure 49), hydrophobic and π−π interactions provide further

the alternating heterocopolymer at intermediate pH values (3.8 < pH < 10.5), and the homopolymer of the of lysine-based monomer in basic conditions. The well-defined nature of the pH-responsive rod-like copolymers with a number-average length distribution of 56 nm will give access to applications in biomedical technologies, as drug and gene delivery vehicles in particular. Release of cargo material in intracellular compartments is known to occur via a decrease of the pH and osmotic swelling. With this in mind, the authors were able to show that by increasing the ionic strength of the phosphate buffer to 25 mM NaCl, the pH stability window for the copolymers was narrowed from pH 3.8−10.5 to 4.2−9.5, while at neutral conditions of pH 7.4 the copolymers disassembled only at salt concentrations > 200 mM NaCl. As expected, an increase in the ionic strength screened the attractive Coulomb interactions. The low polydispersity of the copolymers was suggested to result from a low degree of cooperativity in the polymerization process, which is currently being investigated in more detail using a theoretical model for two-component polymerizations, disclosed by van der Schoot and Jabbari-Farouji.536 The coassembly strategy has been applied by Miravet, Escuder, and co-workers in the development of multicomponent molecular hydrogels that can be switched to onecomponent networks in acidic or basic pH.537 In addition, the group of Hud has reported a similar approach in the development of ultrasensitive and bidirectional pH-responsive supramolecular polymers and hydrogels.538 The monomers were based on nucleic acid base-pairing mimics using a basic triaminopyrimidine and an acidic cyanuric acid derivative as recognition units. The resulting coassembled polymers are most stable when the pH equals the pKa of the monomers but disassemble in response to pH changes near neutrality. Multicomponent self-assembly539 of β-sheet fibrils is a powerful route to produce multifunctional biomaterials540,541 and has been shown to influence the mechanical properties and biological properties of coassembled fibrillized hydrogels.542 Recently, Collier and coauthors reported a strategy to produce β-sheet nanofibers which exhibit smoothly gradated combinations of multiple functional proteins.543,191 Different proteins were obtained via expression in bacteriological cultures, employing “β-tail” tags. These functional building blocks were coassembled into nanomaterials by mixing with additional βsheet fibrillizing peptides, a structural building block with high compositional control. The versatility of the approach was demonstrated using fluorescent proteins, catalytically active enzymes, and protein antigens, which can elicit adaptive immune responses.191

Figure 49. Basic example of a supramolecular polymer based on DNA hybridization. Individual strands (marked by different colors) may have different sequences, complementary to each other, or may have identical self-complementary sequences. Arrows indicate the structural polarity of each DNA strand (5′ → 3′).

stabilization of the assembly.205 DNA hybridization is an enthalpically driven, entropically disfavored process, and its Gibbs free energy can be predicted with excellent accuracy.551−553 The strength of binding between two ssDNA strands grows approximately linearly with their sequence length. At moderate temperatures and for sufficiently long chains, the enormous enthalpic driving force of base pairing overcomes the entropic penalty. A 20-base-pair DNA double strand has a Gibbs free binding energy in the order of 100 kJ/mol at 37 °C, corresponding to an association constant in the order of 1017 M−1. On average, for each added base pair, the association constant increases by about 1 order of magnitude. Therefore, association energies between two long ssDNA strands can easily match and even surpass the energies of single covalent bonds. For this reason, supramolecular polymers based on DNA can be extremely stable, thermodynamically as well as kinetically. Nevertheless, we note that covalent bonds still exhibit much higher mechanical stability as compared to the noncovalent bonding in hybridized ssDNA strands: while the force required to separate two complementary DNA strands grows with strand length, it levels off for sequences longer than 25 base pairs and does not exceed ∼61 picoNewtons even for very long sequences.554 In contrast, breaking a typical covalent bond requires much larger forces, usually in the order of one or more nanoNewtons.555 3.5.1. Simple Hybridization Polymerization. The potential contribution of small synthetic molecules furnished with oligonucleotide handles in supramolecular polymerization was studied many years ago.556−561 The group of Craig reported multiple supramolecular polymers assembled from ssDNA strands.558,560 In their most basic form, each monomer comprises two self-complementary sequences, and hybridization between these sequences leads to polymerization (Figure 49).562 Similarly, alternating copolymers were formed from two different ssDNA strands that have mutually complementary sequences. Such polymer chains can reversibly depolymerize at high temperature or in the presence of a denaturing agent such as urea. It was also demonstrated how the powerful toolbox of molecular biology can be used to manipulate DNA-based supramolecular polymers. For instance, the oligonucleotide strands can be connected via the enzymatic

3.5. DNA-Based Systems

DNA nanotechnology represents a powerful platform for the rational design of self-assembled systems.544−548 Almost all synthetic DNA assemblies rely on Watson−Crick base pairing; the specificity of these interactions renders DNA self-assembly both predictable and programmable. The reliability of Watson− Crick base pairing has enabled researchers to generate complex nanostructures such as DNA-origami.549 Today, synthetic DNA strands with tailor-made sequences are readily available; for instance, 25 nmol of a 60-nucleotide-long single-stranded DNA (ssDNA) molecule with tailor-made base sequence is available for ∼$10 and ships within days.550 Additional functional groups like azide, thiol, fluorescent dyes, or photocleavable modifications can be incorporated into the sequence, which largely widens the scope of possible applications. The cost of 2456


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Figure 50. Hybridization chain reaction (HCR). (a) Two partially self-complementary oligonucleotide sequences, H-1 (green backbone) and H-2 (yellow backbone), form hairpin loops. Black ladders indicate Watson−Crick base pairs, and asterisks indicate sequences that are complementary to each other (a to a*, b to b*, etc.). Although intermolecular hybridization between multiple H-1 and H-2 strands is enthalpically favored over intramolecular looping, the large kinetic barrier of loop opening prevents H-1 and H-2 from polymerizing on the laboratory time scale. (b) In the presence of an initiator strand, I (purple backbone), which is complementary to the single-stranded “toehold” of H-1 (region a), the loop of H-1 opens rapidly, thus exposing unpaired regions c and b*. (c) Regions c and b* trigger loop opening of H-2, thus producing another sticky end with a sequence identical to I. The resulting chain reaction produces an alternating supramolecular copolymer with a molecular weight inversely related to the concentration of I. Adapted with permission from ref 565. Copyright 2004 National Academy of Sciences.

Figure 51. Supramolecular polymerization of DNA tiles can be externally controlled by a DNA-based reaction cycle. (a) General structure of a DNA tile, and schematic of tile polymerization forming tubular structures. (b) Autonomous reaction cycle that is catalyzed by ssDNA strand C. Presence of C catalyzes the release of free product D, which in turn acts as a signal to modulate supramolecular polymerization. (c) AFM image of supramolecular nanotubes formed in the presence of 0.1 equiv of catalyst strand C. No supramolecular polymers were observed in the absence of the catalyst. Adapted with permission from ref 579. Copyright 2013 Nature Publishing Group.

action of a DNA ligase, thus forming covalent bonds between the monomer units and resulting in a continuous DNA double strand.558 Subsequently, an exonuclease enzyme may be used to selectively digest all linear polymerization products, leaving behind only circular polymer chains. Aiming at synthesis of linear dsDNA arrays with programmable length and sequence, Sleiman and co-workers recently reported the polymerization of simple ssDNA563 and dsDNA564 building blocks. The latter were designed to enable control over polymer length via incubation time and assembly protocol (i.e., stepwise addition of alternating monomers). As the sticky ends of the dsDNA monomers were only 10 bases long, hybridization between these building blocks was weak and lead to supramolecular oligomers that were shorter and more disperse than had been expected. However, in the presence of a

DNA ligase, the nascent supramolecular oligomer could be transformed in situ into a continuous dsDNA strand, thus rendering the polymerization process irreversible and enabling growth of long dsDNA molecules with repeating sequences. PCR amplification and further workup yielded monodisperse ssDNA molecules, which were significantly longer than what can be achieved by standard solid-phase oligonucleotide synthesis. 3.5.2. Hybridization Chain Reaction. Dirks and Pierce developed a concept termed hybridization chain reaction (HCR), which is an elegant example of kinetically controlled supramolecular polymerization, representing a noncovalent variant of living polymerization.565 In its simplest form, HCR employs two oligonucleotide strands, H-1 and H-2, which are partially self-complementary. Each of these strands forms a 2457


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DNA nanotechnology enables programmable control over selfassembly under isothermal conditions and combination of supramolecular polymerization with molecular logic. Recently, the group of Seeman reported a cascade reaction that is closely related to HCR but employs DNA tiles as monomer building blocks rather than hairpin loops.580 Interestingly, the system is designed such that a binding event on one side of the tile passes a signal to the opposite side of the same tile using a switch based on toehold-mediated strand displacement. This signal “deprotects” and hence activates that side for binding to the next tile. Analogous to HCR, the binding cascade is triggered by the presence of an “initiator tile”. Seeman’s approach results in isothermal formation of DNA-tile oligomers that have uniform length and controlled sequence of their monomers units. Numerous other DNA-based polymer tubes and filaments have been reported by the groups of LaBean,581,582 Turberfield,583 Majima,584 and Seeman.585 More recently, Yin and coworkers586,587 as well as the group of Willner588 reported design strategies for tubular polymers with programmable diameters, assembled from DNA tiles. Employing a different design approach, Sleiman and co-workers developed circular DNA-based building blocks with triangular or square shape; these undergo controlled polymerization in solution (forming very long supramolecular nanotubes)589−591 as well as on a surface.592 3.5.4. DNA-Origami Polymers. DNA-origami structures are massive (∼5 MDa) yet well-defined, self-assembled systems comprising a long DNA “scaffold strand”, which is folded into a more compact object via hybridization with a large number of shorter “staple strands”.549 Aggregation and unintended polymerization were observed from the inception of DNAorigami; controlled polymerization was later achieved via incorporation of “linker strands” (i.e., strands that were designed to hybridize with two opposite sides of origami monomers), which facilitated interorigami binding in a linear fashion (Figure 52).593−596 When these large and complex origami polymerize, they generate chains that are more massive than virtually any other 1D polymer and which can be highly

kinetically stable intramolecular stem−loop structure (Figure 50a). Potential energy is stored in the unpaired bases of the single-stranded loops and sticky end regions of both strands. Although intermolecular hybridization between H-1 and H-2 is thermodynamically favorable over intramolecular stem−loop formation, the exceedingly slow kinetics of loop opening prevents hybridization of H-1 with H-2 on the laboratory time scale. However, addition of an initiator strand, I, triggers the copolymerization of H-1 and H-2 via the following mechanism: the sequence of I comprises an unconstrained linear region that is complementary not only to the stem of H-1 but also to its single-stranded sticky end (region a on H-1). Initial binding between regions a on H-1 and a* on I drastically increases the subsequent rate of strand exchange, a phenomenon known as toehold-mediated strand displacement.566−568 As a result, the loop opens, thus exposing a linear single-stranded region (comprising c and b*, Figure 50b). This region now triggers loop opening of H-2 (Figure 50c), which exposes a new region (comprising a* and b*) that has a base sequence identical to the initiator strand and is therefore capable of rapidly binding and activating another H-1 loop. The resulting chain reaction produces alternating supramolecular copolymers with an average molecular weight that is inversely related to the concentration of I. HCR enables various functional applications:565,569−576 since only small nonstoichiometric amounts of initiator molecules are required to trigger the polymerization cascade, HCR can be used for sensitive and selective detection of oligonucleotides and other molecules.570−576 Read out of the detection can be achieved, for instance, via gel electrophoresis, fluorescence spectroscopy (if H-1 or H-2 is labeled with a hybridizationsensitive fluorophore), or the polymer’s effect on the optical properties of metal nanoparticles. HCR was also used to create a nanomechanical actuator that utilizes the chain growth to propel forward a load attached to the living end of the polymer.569 This study was inspired by the manner in which certain bacteria use the supramolecular polymerization of actin to generate force for locomotion. 3.5.3. DNA Tiles and Other Self-Assembled Building Blocks. Increasing the complexity of DNA-based polymeric systems, the group of Winfree reported programmable supramolecular polymerization of “DNA tiles”,577 which are rigid platelets, self-assembled from only a few and relatively short oligonucleotide strands (cf. Figure 51a).578 The DNA tiles formed long supramolecular polymer nanotubes upon slow cooling of their aqueous solution. The tubes grew up to several tens of micrometers long and had persistence lengths of approximately 4 μm. This study demonstrated that selfassembly of DNA tiles can generate supramolecular polymer fibers that have structural and mechanical similarities to naturally occurring proteinaceous polymers (cf. section 2). Recently, Winfree and co-workers demonstrated that the same type of DNA-tile polymerization can be controlled by an additional DNA-based reaction cycle (Figure 51b).579 This reaction cycle is an entropically driven sequence of strand displacement reactions, whichin the presence of a catalyst ssDNA strand (C)produces a product ssDNA strand (D). Depending on the design of the system, strand D can subsequently serve either as a “deprotecting agent” to activate binding between DNA tiles or as a linker between places. In both cases, in situ formation of D acts as a signal to modulate the formation of the supramolecular polymer (depicted in Figure 51c). Such an upstream reaction cycle based on dynamic

Figure 52. DNA-origami polymers held together by oligonucleotide linker strands. Schematic depiction and corresponding AFM images of (a) stair-like DNA-origami polymer and (b) a functional DNA-origami polymer that serves as a template to create a linear array of quantum dots (discernible as two bright spots flanking the rectangular hole in each origami monomer). Reprinted with permission from refs 594(a) and 596 (b). Copyright 2010 American Chemical Society and 2014 Royal Society of Chemistry. 2458


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Figure 53. Massive supramolecular polymers based on shape-complementary three-dimensional DNA origami. (a) Schematic illustration of the principle of reversible binding between shape-complementary building blocks. Intermolecular binding is driven by π−π and hydrophobic interactions between the exposed “blunt ends” (top and bottom ends of the red and blue helices), which comprise the surface of the shape-complementary origami object. Molecular models and negative stain TEM images of (b) linear single-stranded filaments and (c) two-stranded filaments. Reversible assembly/disassembly of the polymer can be controlled by altering the concentration of Mg2+ ions. Scale bars: 50 nm. Adapted with permission from ref 21. Copyright 2015 The American Association for the Advancement of Science.

rigid. Interestingly, each monomer offers a large number of sites that are fully addressable, enabling site-specific attachment of various functional moieties, fluorescent probes, reactive groups, or handles for further noncovalent attachments. For instance, DNA-origami polymers were used to bind and spatially arrange single-walled carbon nanotubes595 and quantum dots.596 Such systems may have potential applications for the generation of nanoscopic electrical circuits and as optoelectronic, plasmonic, and electrochemical devices. Folding of DNA is not limited to compact two-549 and threedimensional597 origami but also enables formation of very long (pseudo-1D) tubes and beams.546 Therefore, high-aspect-ratio nanostructures can be obtained even when the number of assembling units is small. The group of Shih designed DNAorigami nanotubes that comprised a bundle of six parallel double helices;598,599 the tubes undergo controlled (hetero-) dimerization, creating monodisperse fibers that are about 800 nm long and 8 nm wide. At high concentration, these nanostructures align and form a liquid crystalline phase, which can act as a matrix that orients guest macromolecules in a preferred direction. The material was found to be compatible with solubilized membrane proteins, and it was used to demonstrate structural elucidation of a membrane protein via NMR.599

Polymerization of DNA-based systems is also possible without Watson−Crick base pairing as the primary binding interaction between monomer units.561,549,600,21 The group of Dietz recently described the self-assembly of shape-complementary multilayer597 DNA-origami for the construction of switchable nanoscopic devices and polymeric structures (Figure 53).21 Instead of Watson−Crick hydrogen bonds, polymerization was driven by π−π and hydrophobic interactions between the blunt ends of exposed DNA helices, which decorated the origami surfaces (Figure 53a). This type of binding is sensitive to the concentration of cations, as these are required to attenuate the electrostatic repulsion between aligned negatively charged DNA helices. Although blunt-end stacking is nonspecific, the origami monomers were designed such that the exposed helices formed patterns that fit to each other like a plug into a hole. Thus, only geometrically matching surfaces facilitate cooperative binding between multiple blunt ends, which is required to overcome electrostatic repulsion. This innovative shape recognition enabled specific and orientationally constrained binding between origami monomers. Assemblies of shape-complementary DNA origami allowed reversible switching, induced by changes in temperature or ionic strength. One type of shape-complementary DNA-origami bricks polymerized into massive, micrometerlong rods, which could be reversibly disassembled via lowering 2459


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(2) Large hydrophobic molecules containing extended πconjugated surfaces form exceptionally stable aggregates in water, resulting in high thermodynamic and kinetic stability. Besides their remarkable robustness, π-stacking molecules provide supramolecular order, electronic coupling between chromophores, and facile quantification of the polymerization process. (3) Host−guest interactions, which are also widely found in biological self-assembly, combine high specificity and large association strength with size self-selection. (4) Small peptides and peptide amphiphiles are a widely applicable set of building blocks for the design of functional supramolecular soft matter in water with stimuli-responsive and programmable properties. The combination of reversible covalent bonds and noncovalent interactions can be used for kinetically controlled product formation, rather than structures that are in thermodynamic equilibrium, with exciting opportunities in complex molecular networks and self-synthesizing materials. (5) DNA-containing molecules may enable rational design of highly robust supramolecular polymers. In light of dropping costs of synthetic DNA molecules, supramolecular polymerization may see a renaissance of DNA-based monomeric building blocks, especially when structural complexity and programmability are desired. Importantly, kinetic and thermodynamic parameters of DNA supramolecular polymerization can be predicted, rationally designed, and modified, for instance, via toehold-mediated strand displacement. The raised interest in aqueous supramolecular polymers has resulted in intriguing functional materials, with applications in diverse fields, such as optoelectronics (displays, light harvesting, and water splitting), sensing, separation, actuation, and molecular logic. Biomedical applications, such as tissue engineering, drug delivery, gene transfection, and diagnostics, are among the most promising applications for aqueous supramolecular polymers. For instance, supramolecular polymers may be used to construct artificial tissues that can be easily degraded by the organism over time. For the further advancement of the field, detailed studies into supramolecular polymerizationespecially regarding its kinetic aspects and nanomechanical propertiesare important. For instance, the paradigm of thermodynamically equilibrated supramolecular polymers has been challenged in recent years by the realization that supramolecular polymerization of small molecules can take place under kinetic control. Water is a particularly suitable medium for kinetically controlled supramolecular polymerization, since hydrophobic aqueous selfassembly often involves large kinetic barriers. Improved mechanistic understanding will enable rational design of novel supramolecular polymers with desired functionality. Can aqueous supramolecular polymers rival and replace conventional covalent polymers? Achieving high robustness in supramolecular polymers (high association constants, high mechanical stabilities) is an important precondition to enable functional materials applications. Simultaneously, it is crucial to retain the adaptive properties that make noncovalent systems unique (stimuli-responsiveness, adaptivity and self-healing). Implementing biomolecular building blocks may enable supramolecular polymers to respond to various biological signals. By combining these properties with functionality, aqueous supramolecular polymers will grow far beyond academic curiosity-driven research and enter large-scale commercial applications.

the Mg2+ ion concentration. (Figure 53b). A second type of origami monomers polymerized into two-stranded polymers that have structural similarities to actin filaments (Figure 53c). Temperature-dependent switching of the shape-complementary binding motif is very reliable: binding within a discrete origami structure could be robustly and rapidly switched on and off over more than 1000 heating and cooling cycles without significant loss in responsiveness. Overall, DNA nanotechnology enables predictable creation of supramolecular polymers on various levels of size and complexity. Notably, toehold-mediated strand displacement offers fascinating potential for introducing Boolean logic601 into supramolecular polymerization, thus creating new forms of programmable polymers that exhibit multiple responsiveness to various input signals. Despite their large thermodynamic stability at room temperature, supramolecular polymers based on DNA hybridization are intrinsically reversible. For instance, as a result of the large entropic penalty, DNA hybridization is strongly temperature dependent. Thus, even long doublestranded segments can be dehybridized at high temperatures and low ionic strength.

4. CONCLUSIONS AND OUTLOOK Since the early studies describing “reversible polymers”206 and “polymers of supramolecular nature”1 the field of supramolecular polymers is expanding with increasing pace. Advantages of supramolecular polymers include superior processing, facile material fabrication and recycling, as well as stimuli-responsive and self-healing properties. Supramolecular polymerization is particularly intriguing in aqueous solution, since water has unique properties (e.g., the hydrophobic effect) and plays a pivotal role in biological systems. In fact, Nature provides the ultimate proof that functional supramolecular polymers not only are feasible but can be superior to conventional polymers in many ways. Supramolecular polymers are actively involved in central biological functions, including cell division and migration, structural reinforcement, signaling, transport, actuation, and propulsion. Natural supramolecular polymers exhibit cooperatively controlled formation, regulation via external signals, self-organization, and structural polarization. Some of these properties give rise to fascinating dynamic phenomena like treadmilling, dynamic instability, and the ability to combine high mechanical robustness with rapid stimuli responsiveness. To date, both the complexity and functionality of the supramolecular polymers found in Nature are unmatched by any synthetic system. On a positive side, the existence of supramolecular biopolymers opens two important avenues in noncovalent synthesis: first, it enables us to directly utilize and manipulate these systems for the production of functional biomaterials. Second, supramolecular biopolymers represent a source of inspiration for the design of synthetic systems that mimic their complex structure and function, resulting in nanomaterials with off-equilibrium dynamic properties, enabling autonomous functions related to self-healing, actuation, and processing of information. Synthetic organic chemistry provides access to a massive number of functional groups with tailor-made properties and different binding motifs. (1) H-bonding motifs provide directionality and thus enable rationally designed reversible polymers. However, there is competition in H bonding with the aqueous environment, demanding the design of hydrophobic pockets around the H-bonding motifs to ensure directionality. 2460


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AUTHOR INFORMATION

was awarded the University Academic Award in 2013 for best Ph.D. thesis at the TU/e. She moved to the Wyss Institute of Harvard University in Boston as a NWO Rubicon and Human Frontier Science Program postdoctoral fellow in the lab of Prof. William M. Shih. She studies DNA as programmable biomaterial to design immune responses and assemble into multimodal nanoparticles. In January 2017 she will start as tenure track Assistant Professor in the Materials Science and Engineering Department at EPFL, Switzerland.

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Pol Besenius studied Chemistry at the Vienna University of Technology in Austria and at the University of Strathclyde in Glasgow, Scotland. He received his Ph.D. degree from the same institution in 2008, under the supervision of Prof. Peter Cormack and the late Prof. David C. Sherrington FRS, in collaboration with Prof. Sijbren Otto and Prof. Jeremy K. M. Sanders FRS at the University of Cambridge. As a Marie-Curie Intra-European Fellow he undertook postdoctoral studies at the Eindhoven University of Technology and Institute for Complex Molecular Systems with Dr. Anja Palmans and Prof. E. W. “Bert” Meijer. In 2011 he moved to the University of Münster to set up an independent research group at the Organic Chemistry Institute and the Center for Nanotechnology (CeNTech), supported by a Liebig Fellowship from the Fonds der Chemischen Industrie; he was also elected as young fellow to the North RhineWestphalian Academy of Sciences and Arts. In 2015 he took up a Professorship at the Institute of Organic Chemistry at the University of Mainz. His research interests include macromolecular chemistry, self-assembly in water, and supramolecular nanomaterials and hybrid materials.

Elisha Krieg studied Chemistry at the University of Cologne and at the Weizmann Institute of Science. He received his Ph.D. degree in Chemistry (Shimon Reich Memorial Prize) at the Weizmann Institute in 2013 under the supervision of Prof. Boris Rybtchinski. His research focused on the construction of materials based on self-assembled perylene diimide amphiphiles. These molecules have large hydrophobic surfaces, thus generating unconventionally stableyet stimuliresponsivenoncovalent materials in aqueous medium. During his studies he received fellowships from the Studienstiftung des deutschen Volkes and the Minerva Foundation. He is currently a Human Frontiers Science Program postdoctoral research fellow in the group of Prof. William M. Shih at Harvard University. He is interested in using DNA Nanotechnology to develop self-assembled nanodevices that can be used for characterization and manipulation of biological macromolecules.

Maartje Bastings studied Biomedical Engineering at the Eindhoven University of Technology (TU/e) and graduated Cum Laude in the group of Prof. E. W. “Bert” Meijer, where she continued her Ph.D. program funded by a Toptalent Fellowship from the Dutch Science Foundation (NWO), cosupervised by Dr. Patricia Y. W. Dankers. Her research focused on the understanding of multivalent binding mechanisms for directed targeting and the development of supramolecular biomaterials, and she received her Ph.D. degree in 2012. She

Boris Rybtchinski received his B.Sc. degree from Kiev State University in Ukraine. He then moved to Israel, where he earned his Ph.D. degree at the Weizmann Institute (with Prof. D. Milstein). He conducted postdoctoral research at Northwestern University (with Prof. M. Wasielewski) and joined the Weizmann Institute in 2005. Currently, he is an Associate Professor at the Department of Organic Chemistry. 2461


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LMWG = low molecular weight gelator LUV = large unilamellar vesicles MS = mass spectrometry MT = microtubule MTX = methotrexate NMR = nuclear magnetic resonance nt = nucleotide NTA = nitrilo triacetic acid OEG = oligo(ethylene glycol) OPE = oligo(phenylene ethynylene) OPV = oligo(phenylenevinylene) PBS = phosphate-buffered saline PCR = polymerase chain reaction PDI = perylene diimide PEG = poly(ethylene glycol) PMI = perylene monoimide QD = quantum dot PSS = poly(4-styrenesulfonate) RNase = ribonuclease SEM = scanning electron microscopy SNP = superparamagnetic ironoxide nanoparticle STORM = stochastic optical reconstruction microscopy STM = scanning tunneling microscopy TEM = transmission electron microscopy TOF = turnover frequency TON = turnover number THF = tetrahydrofuran UV/vis = ultraviolet/visible spectroscopy vdW = van der Waals vol % = volume percent WAXS = wide-angle X-ray scattering wt % = weight percent

He has received a number of awards, including a Kennedy Prize, a Rothschild Postdoctoral Fellowship, an Israel Parliament (Knesset) Prize of Excellence, and the Sir Charles Clore Prize and delivered a 2013 Werdelmann Lecture. His research interests include fundamental and applied aspects of water-based noncovalent nanomaterials.

ACKNOWLEDGMENTS E.K. and M.M.C.B. gratefully acknowledge support of the Human Frontier Science Program. B.R. acknowledges support from the Israel Science Foundation, Minerva Foundation, USIsrael Binational Science Foundation, Gerhardt M. J. Schmidt Minerva Center of Supramolecular Architectures, and the Helen and Martin Kimmel Center for Molecular Design GLOSSARY aa = amino acid A, D, E, F, G, H, I, K, L, R, S, T, V, W, Y = alanine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, arginine, serine, threonine, valine, tryptophan, tyrosine Ala, Cha, p-Cl-Phe, Gln, Glu, Leu, Lys, 1-Nal, Phe, Ser, Trp, Tyr = alanine, cyclohexylalanine, p-chlorophenylalanine, glutamine, glutamic acid, leucine, 1-naphthylalanine, phenylalanine, serine, tryptophan, tyrosine ADP = adenosine diphosphate AMP = adenosine monophosphate AQ = anthraquinone-2-carboxylate ATP = adenosine triphosphate AFM = atomic force microscopy Boc = tert-butyloxycarbonyl BTA = N,N′,N″-trialkyl-benzene-1,3,5-tricarboxamide bp = base pair CB = cucurbituril CD = circular dichroism or cyclodextrin cgc = critical gelation concentration CP-MAS NMR = cross-polarization magic angle spinning nuclear magnetic resonance cryo-SEM = cryogenic scanning electron microscopy cryo-TEM = cryogenic transmission electron microscopy Da = Dalton DCL = dynamic combinatorial library DCM = dichloromethane DHFR = dihydrofolate reductase DNP = dinitrophenol DOSY = diffusion-ordered spectroscopy DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid dp = degree of polymerization DTPA = diethylene triamine pentaacetic acid EM = electron microscopy Fmoc = fluorenylmethoxycarbonyl FRET = Förster resonance energy transfer FTIR = Fourier transform infrared spectroscopy GUV = giant unilamellar vesicles HBC = hexabenzocoronene HCR = hybridization chain reaction H bond = hydrogen bond HFIP = Hexafluoroisopropanol HG = host−guest HPLC = high-performance liquid chromatography IgE = immunoglobulin E IR = infrared

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