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Designer Peptide Amphiphiles: Self-Assembly to Applications Antara Dasgupta, and Debapratim Das Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.9b01837 • Publication Date (Web): 22 Jul 2019 Downloaded from pubs.acs.org on July 23, 2019

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Designer Peptide Amphiphiles: Self-Assembly to Applications Antara Dasgupta† and Debapratim Das‡*

†Eris

Lifesciences, Plot No. 30 & 31, Brahmaputra Industrial Park, Amingaon, North

Guwahati, Guwahati, Assam 781031.

‡Department

of Chemistry, Indian Institute of Technology Guwahati, Assam-781039,

India.

ACS Paragon Plus Environment

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ABSTRACT

Peptide amphiphiles (PAs) are extremely attractive as molecular building blocks especially in the bottom-up fabrication of supramolecular soft-materials and have potential in many important applications across various fields of science and technology. In recent years, we have designed and synthesized a large group of peptide amphiphiles. This library of PAs have the ability to self-assemble into a variety of aggregates such as fibers, nano-sphere, vesicles, nano-sheet, nano-cups, nano-rings, hydrogels and so on. The mechanism behind the formation of such a wide range of structures is intriguing. Each system has its individual way of aggregation and results in assemblies with important applications in the areas including chemistry, biology and material science. The aim of this feature article is to bring together our recent achievements with designer PAs with respect to their self-assembly processes and applications. Emphasis is given on the rational design, mechanistic aspect of the self-assembly processes and the application of these PAs. We hope that this article will provide a conceptual demonstration of the different approaches taken towards the construction of these task-specific PAs.


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INTRODUCTION

Self-aggregation of small molecular components is a spontaneous process/phenomenon utilizing various non-covalent interactions viz. hydrophobic interaction, hydrogenbonding,  stacking, metal-ligand complexation, van der Waals forces, cation- or anion- interaction etc.1-2 The philosophical root of supramolecular chemistry was developed by Emil Fischer way back in 1894 through his “lock and key” model for enzymesubstrate interactions.3 The introduction of this essential principles of molecular recognition allowed us to understand and unveil complex biological systems. Nature uses these supramolecular forces with ultimate precision and efficiency to create extremely complex systems. One of the most prominent example is the plasma membrane formed by simple small amphiphilic molecules.4 The perception of compartmentalization starts as the membranes are created. The ideal use of functional groups to create an optimal hydrophilic-lipophilic balance (HLB) within the amphiphiles, further allow them to selforganize into a membrane which can hold the key of life. Over the last century, the


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chemistry of non-covalent bonds has developed as a distinctly separate interdisciplinary branch of science.5

Amphiphilic molecules are omnipresent in nature and whilst mimicking the natural systems, it can easily be understood that a subtle change in the structure or precisely in the HLB of these amphiphiles can cause a drastic change in the biological phenomenon.6 Structural diversity of amphiphilic molecules dictate the mode of their self-assembly process and lead to the formation of variety of self-assembled aggregates like, micelles, microemulsions, vesicles, liquid crystals, fibres, tapes, gels to name a few.7-9 The selfaggregation behavior of amphiphiles gets significantly affected by minute changes in the structure. For example, reducing the hydrophobic chain of a surfactant simply by removing an ethylene group can enhance the critical aggregation concentration by an order of magnitude.10 Similarly, minor changes in the head group can lead to drastic changes in the self-assembly size and property.11 Manipulating the structures of these amphiphilic molecules thus provides control over their aggregation pathway and leads to soft-materials with tunable properties. As a result, it can be said conclusively that the key


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behind preparation of materials with targeted application remains with the rational design of the constituent amphiphilic molecules.

One important class of amphiphilic molecules are the peptide amphiphiles (PA).9,

12-14

Conjugating hydrophilic peptide sequences to lipophilic groups or arranging amino acids in a peptide sequence in a way to obtain hydrophobic and hydrophilic ends lead to the construction of PAs. The major advantage of PAs is their probable biocompatibility and bio-degradability as they are prepared of natural amino acids. Additionally, the wide range of functional groups available with the natural amino acids allows one to design PAs with desired functionality. The HLB can easily be manipulated either by proper sequencing of the amino acids or through incorporation of other hydrophobic groups. Over the last couple of decades, the research on PAs has experienced a strong upsurge. Many new rationally designed PAs have come up, not only to understand the self-assembly behavior but also to construct novel smart soft-materials.15-19 Combining peptide sequences with other functional groups to design new PAs lead to the preparation of new soft-materials with unprecedented properties and applications. Application of PA-based soft materials


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ranges from drug-delivery, wound healing, tissue engineering, enzyme protection, template synthesis of nano-materials, sensing, organic-electronic devices and so on.12, 14, 20-21

An overview about the peptide amphiphiles, their self-aggregation and consequent

nano-structures as well as applications is summarized in Scheme 1.


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Scheme 1. Overview of the PA classification, different self-assembled nano-structures formed and applications of PA.

Over the years, our group is focused on the way to designing of various types of PAs to understand/create controlled self-assembled systems for a variety of applications. The present feature article is an account of our research work involving designer PAs and tailoring of their self-assembly process for targeted applications.


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PEPTIDE AMPHIPHILES: THE CLASSIFICATION AND DESIGN

Peptide amphiphiles can be classified into three categories, ie, 1) amphiphilic peptides; 2) lipidated peptide amphiphiles; and 3) supramolecular peptide amphiphiles conjugates. In this section, these different classes of PAs are discussed following the structural aspect.

Amphiphilic Peptides: Amphiphilic peptides are a class of PAs which are made of amino acids only.9 In principle, such PAs are made of a combination of hydrophobic and hydrophilic amino acids. Nature utilizes this phenomenon to create membrane proteins which are capable of folding in a way to create an entirely hydrophobic surface with a hydrophilic interior and thereby enabling themselves to assimilate into the lipid bilayer of membranes.22-23 Several peptide based toxins and antibiotics are functional through this mechanism.24-25 Similar amphipathic mechanism is also adopted for construction of cell penetrating as well as antimicrobial peptides and in recent years there has been a surge to prepare such sequences.26-28 Studies involving the design, synthesis of amphiphilic


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peptides and their interaction with membrane could eventually lead to discovery of effective therapeutic agents. The self-assembly of these amphiphilic peptides is another important aspect leading to creation of new soft-materials with potential to various applications including biomedical. For example, self-assembly of these PAs can be finetuned to create physical hydrogels or vesicular structures which can be used for drug delivery or tissue engineering efficiently.29-30

Amphiphilic peptides can be of two different sub classes, a) peptides containing alternating hydrophilic/hydrophobic amino acid residues, and b) a long hydrophobic stretch of amino acids connected to a hydrophilic sequence. The properties and aggregation behavior of these designer amphiphiles differ considerably.


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Scheme 2. Structures of some amphiphilic peptide sequences.

Peptides comprising of repetitive dyads of hydrophobic and hydrophilic residues often tend to adopt -pleated sheet like structures. Such sequences create two faces of a strand, a hydrophobic one where all the hydrophobic side chains are directed while the other face is comprises of the polar side chains of the amino acids (Scheme 1). While constructing all amino acid PAs, this is the most common platform. A plethora of such


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peptides and their self-assemblies are reported in literature. A series of such PAs are reported by Zhang et al.(1-3, Scheme 2).31 In all of these peptides, the amphiphilicity was generated by alternate use of hydrophilic and hydrophobic amino acid residues. These sequences self-assemble into nano-fibres and a higher order aggregation of the nanofibers lead to hydrogelation. Another interesting subclass of such PAs are the 20amino acid sequence developed by Schnieder et al.32-33 By introducing a DPro-LPro linker in between two stretches of alternating Lysine and Valine, a Type-II’ -turn is created (4, Scheme 2). These peptides are highly soluble in water or low pH and remain as low viscosity liquid. At this state, the peptide adopts no particular secondary structure and remain as random coils due to electrostatic repulsion of the cationic groups. However, under basic pH as the solubility of the peptide decreases due to deprotonation of the free amines, the peptides folds in a fashion to create antiparallel -sheet structures involving a -hairpin formation at the DPro - LPro region. The folded peptide intermolecularly selfassemble to form a hydrogel.32 Several minor alteration in the sequence are reported by the same group and have shown that the folding of these peptides can be regulated by


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changing the temperature, ionic strength of the system or even by incorporation of metal ions.33-35

The second sub-class of amphiphilic peptides comprises of two segments, a polar and a hydrophobic sequence. While the polar residues act as a head group, the hydrophobic sequence can be considered as the tail of the amphiphile (Scheme 1). Though the structure of such peptide resembles that of typical surfactants, their self-assembly mechanism can be distinctly different. The major reason behind such difference is the involvement of hydrogen bonding which are uncommon for classical surfactant molecules. In general, the tail component of these PAs contain 3-9 amino acid residues, as further increasing the number decreases the solubility of the PA in aqueous medium. On the other hand, decrease in the length results in enhanced solubility and consequently the possibility of self-aggregation decreases. The head group often carries charged groups and an appropriate HLB can be achieved with proper adjustment in the number of hydrophilic and hydrophobic residues. One such series was studied by Koutsopoulos group (5-8, Scheme 2).29 Analyses of the positively charged peptide amphiphile


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formulations (7-8) showed the formation of individual nanovesicles while the negatively charged PAs (5-6) self-assembled into clusters of nano-vesicles which upon drying organized into necklace-like arrangements. It was proposed that prior to necklace formation, the negatively charged peptide formed loosely bound clusters and during quick drying process, these clusters disassemble and spread on the negative surface of mica leading to the formation of necklace-like formation. Theoretical calculation showed that 20 nanovesicles of 5 with a diameter of 28 nm and 9 nanovesicles of 6 with a diameter of 44 nm are gathered together to form clusters of 97 and 120 nm respectively and these values correlate well with the microscopic analyses. Another similar series was reported by Zhang where one to two residues of lysine or histidine were attached to the A6, L6, and V6 sequences (8-14).36 In aqueous medium, ordered structures with dynamic behaviors were formed by these PAs. At pH below the pI values of the PAs, transmission electron microscopic (TEM) analyses of quick-frozen samples revealed the presence and interplay of nanotubes and nano-vesicles within the system. Above the pI, these nano-structures were not seen and further self-assembly resulted into large membranous sheets.36 The self-assembly process is an entropy driven phenomenon where the individual monomers


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pack together to keep their hydrophobic tails away from water. The negatively charged PAs formed bilayer structures and it is also likely that the cationic PAs may also form a curved peptide bilayer. The peptides stack within this curved bilayer in a way to expose their hydrophilic heads toward water while the hydrophobic tails remain in the lipophilic region of the bilayer. Similarly, Hamley and coworkers reported self-assembly and their applications of similar PAs like A6R, A6RGD etc.37-38

Lipidated Peptide Amphiphiles: This group of PAs consists of most representatives in literature.39-40 Post-translational modification of signal transduction proteins with lipid groups are common. One or two lipid groups (palmitoyl, farnesyl, geranylgeranyl etc.) get attached to the C-terminal amino acids of the proteins which help them to anchor at the cell membrane.41-42 In general, designer peptide amphiphiles in general, comprise of the hydrocarbon chains at the N-terminal while the peptide sequence at the C-terminal serves as the polar head group. However, examples of PAs are also available where the Nterminal is conjugated with polar charged group (quaternary ammonium) while the Cterminal is connected with hydrocarbon chains.43-44 Structurally, these group of


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amphiphiles resemble with typical phospholipid or surfactants. They self-assemble above a critical aggregation concentration (CAC) similar to critical micelle concentration (CMC) of a surfactant. Below the CAC, the molecules remain in monomeric state.

Figure 1. (A) Chemical structure of the peptide amphiphile 15, highlighting five key structural features. (B) Molecular model of the PA showing the overall conical shape of the molecule going from the narrow hydrophobic tail to the bulkier peptide region. (C)


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Schematic showing cylindrical micelle formation through self-assembly of 15. Reproduced with permission from Hartgerink, J. D., et al. Science 2001, 294, 16841688.45 Copyright 2001, AAAS.

An excellent example of a single tail lipidated PA was reported by Stupp et al.45 There are five different structural elements in the design of the PA (15, Figure 1). A palmitoyl group at the N-terminal acting as the hydrophobic part and connected to the second region containing four cysteine residues, providing an oxidative polymerization site. Then comes a flexible linker of three Gycines followed by the fourth section, a single phosphorylated Serine residue. The presence of the phosphoserine residue is for binding with calcium ions and to promote mineralization. The fifth and final region is a cell targeting RGD motif. The self-assembly of this PA was used for effective mineralization which is discussed in the application section of this article. This amphiphile is not only a classic example, it is also a tutorial for how to design a PA for a specific application.


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Our group is involved in designing lipidated PAs for various applications. Some of the representative examples are shown in Scheme 3. Compound 16 is a simple derivative of Fmoc protected Lysine where hexadecyl chain is coupled with acid group of the amino acid.46 The long chain alkyl group provides the hydrophobic interaction site and the side chain amine functionality of the amino acid acts as the head group providing the solubility in water as it remains protonated in neutral condition. However, due to the presence of hydrophobic tail as well as the fused -system in the form of Fmoc group, the molecule tends to aggregate at higher concentration. It is the combination of appropriate HLB of the molecule,  stacking of the Fmoc groups, and hydrogenbonding that allows the formation self-aggregated helical fibers by 16. Interestingly, though the L analogue formed left handed helical nano-fibers, the D enantiomer resulted into right handed helical fibers. The helical nature of the fibers is a result of the supramolecular chirality translated from the chiral center of Lys residue.

Lipidated PAs can also contain more than one lipid groups. However, it is crucial to keep proper HLB by varying the head group polarity or reducing the overall


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hydrophobicity. In a detailed study involving seven different mono and doubly lipidated peptide amphiphiles (17-23), we have described the crucial role of hydrophobicity toward self-assembly and related morphology.47 The doubly lipidated PAs selfaggregated to form - type structures ranging from twisted nano-tapes/ribbons to dense helical fibrillar networks while the single chain and non-lipidated aromatic moiety containing PAs having similar head group failed to show any dominant structure. The effect of number of aliphatic chain as well as chain length was also studied by BiancoPeled group using (Gly-Pro-Hyp)4-IVH1 peptide as the head group of the PAs.48 The details of these results are discussed later in section, “Factors Controlling the Selfassembly process ".


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Scheme 3. Chemical structures of some lipidated PAs.

Another interesting design to promote self-assembly of lipidated PAs come from the introduction of aromatic groups in between the peptide sequence and the hydrocarbon chains. Use of fused aromatic groups like naphthalene, pyrene, Fmoc, Arylenediimides (ADI) etc. in short peptides is a common approach toward construction of peptide based hydrogels.13-14, 49-51 Introduction of such aromatic groups enhances the hydrophobicity as well as provides the possibility of strong  stacking between the molecules. ADI are common choice for this purpose not only for their  stacking ability but also because of the fact that these groups have tremendous potential toward applications in


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organic electronics and chemosensor development.52-54 One such representative of this type, is compound 24.55 In this PA, a hexyl chain is attached to one end of naphthalenediimide (NDI) while the other end of NDI is functionalized with a RGDS sequence. In order to maintain the HLB, one lysine is introduced in between RGDS and the NDI group. PA 24 goes through a three stage self-assembly process leading to a hydrogel (discussed in detail under section, “stepwise assembly”). Along with hydrogen bonding and hydrophobic interactions, -stacking plays crucial role in the self-assembly processes. Perylenediimide (PDI) can also be incorporated in place of NDI to construct such type of lipidated PAs. Compound 25 was designed to create a self-assembled structure in presence of Pd2+ ion and thereby the emission of the PDI group gets quenched.56 In presence of CN- ions the aggregated structure breaks and the system regains its emission property. The aggregation-disaggregation directed change in fluorescence was successfully used for detection of Pd2+ and CN- ions in solution and the details are discussed later.


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Incorporation of pyrene rings at the N-terminal of a hydrophilic amino acid sequence provides the additional benefit of stacking in the hydrophobic region which stabilizes the self-aggregation. Peptides 26 and 27 contain pyrene butanoic acid connected to FFK and KC sequences. Both the peptides self-assemble to form nano-fibrous networks through self-aggregation. PA 26 formed hydrogel in 1:1 water–acetonitrile and was found to be an effective sensor for picric acid.57 The self-assembly of 27 leads to a hydrogel with unique confinement property and is discussed later in the “hydrogel” section.58

Amphiphiles with two polar heads at the two ends of a lipid are called bola amphiphile. Peptide based bola amphiphiles are not as common as the other types. Recently, our group demonstrated solvent polarity induced morphogenesis of a bola-PA.59-60 Compound 28 was designed by incorporating PDI group as the hydrophobic and stacking unit while two FF sequences were connected at the two imide positions of the PDI. The molecule showed a wide range of self-aggregated morphology including


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nanofiber, nano-ring, hollow sphere, nano-cup etc. in different solvents (the details of the morphogenesis is discussed under section, Self-Assembly of Peptide Amphiphiles).

Supramolecular PAs

In recent past, a new research area by the name, supramolecular amphiphile, has developed by combination of traditional amphiphiles and supramolecular chemistry.61 In contrast to traditional amphiphiles, in this case, an amphiphilic structure is constructed by combining two separate molecules through supramolecular interactions or dynamic covalent bonds. This approach provides flexibility to construct various amphiphilic structures from one particular component. Moreover, supramolecular amphiphiles are very useful towards fabrication of soft-materials with high structural complexity and stimuli responsiveness.7, 62 Use of different macrocyclic hosts like, cyclodextrins,63 calixarenes,64 crown ethers,65 pillararenes66 and cucurbiturils,67-68 are the primary approach to construct such supramolecular conjugates. However, hydrogen bonding and charge transfer (CT) complexation between electron donor and acceptor are also successfully used to create supramolecular amphiphiles.69-70


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Though a plethora of examples is present in the literature about supramolecular amphiphiles, one, comprising a peptide segment are not very common yet. As mentioned earlier, design of supramolecular PA commonly lies on the utilization of the host-guest chemistry of different macrocyclic hosts. In one of the early examples, Kros et al. reported the controlled release from a peptide decorated vesicle through pH sensitive orthogonal supramolecular interactions.71 The surface of a vesicle formed by a lipid functionalized cylodextrin was covered with an N-terminal adamantane functionalized -sheet forming octapeptide (VE)4. The decoration was achieved through inclusion complex between adamantane units of the peptide and cyclodextrin. Three different orthogonal noncovalent interactions were used to construct the two component vesicle: (a) hydrophobic interactions of the lipid group; (b) host-guest complexation of -CD and adamantane; (c) hydrogen bonding in the peptide.

In this regard, cucurbit[8]uril (CB[8]) provides an excellent platform to design a three component amphiphilic structure as it can accommodate two different guests inside its hydrophobic cavity and acts as a supramolecular handcuff (Scheme 4A).72-73 The


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interaction of CB[8] with asymmetric viologen containing amphiphiles in presence of an appropriate second guest leads to the formation of unilamellar vesicles.74-76 Utilizing the ternary complexation of CB[8] we have constructed a supramolecular PA which selfassemble to form vesicles.77 A pyrene containing hydrophilic short peptide sequence (29) was supramolecularly conjugated with an asymmetrical viologen-amphiphile using CB[8] as the host. The CT complexation between pyrene and viologen inside CB[8] cavity is one of the key factors facilitating the construction of the supramolecular peptide amphiphile. This concept was further extended to construct a light responsive vesicle. In this work, in place of pyrene, a photo-isomerizable group in the form of azobenzene was connected at the N-terminal of a pentapeptide (30).78 The photo-triggered cis-trans isomerization of the azobenzene dissociates the ternary complex leading to disruption of the vesicle. Similar concept of CB[8] assisted ternary complexes was also further used to construct a peptide-polymer amphiphilic conjugate for efficient encapsulation of fibroblast growth factor.78


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Scheme 4. A) Chemical structure of CB[8] and schematic presentation of ternary complexation by CB[8]. B) Pictorial presentation of formation of supramolecular amphiphile using CB[8] ternary complexation and the chemical structures of the peptides used for that purpose. Adapted with permission from Jiao, D., et al. Angew. Chem. Int.

Ed. 2012, 51, 9633-9637,77 and Mondal, J. H., et al. Soft Matter 2015, 11, 4912-4920.78 Copyrights 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, and 2015 Royal Society of Chemistry.


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SELF-ASSEMBLY OF PEPTIDE AMPHIPHILES

Factors Controlling the Self-assembly process.

The formation of these ordered nanostructures pertains to the synergistic effect of various intermolecular non-covalent interactions, including hydrogen-bonding, - stacking, electrostatic, hydrophobic, and van der Waals interactions. Therefore, the self-assembly process is mainly driven by thermodynamics; however, kinetics is also a critical factor in structural modulation and function integration. There are several driving forces that govern the self-assembly processes of PAs. However, three major energy contributions are coming from the hydrophobic interactions, hydrogen bonding, and the electrostatic repulsion from the charged amino acid residues of the head group of the PA.15 Though the first two are attractive forces promoting the assembly, the electrostatic forces acting at the head groups are dissociative in nature. Thus, a delicate balance is required in the design of the PA in order to facilitate the assembly process. The final assembly structure, shape, size and the interfacial curvature depends on this balance. Like any amphiphilic


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structure, HLB of PAs is also crucial in determining the aggregation pathway. The presence of a hydrophobic tail in a PA increases the thermal stability.79 The secondary structures produced by a peptide becomes more stable when a lipid group is attached to the peptide. Van Hest et al. have shown that the presence of n-alkyl chains to a known -sheet forming peptide (KTVIIE) enhances the thermal stability of

the assemblies

without affecting the final morphology.80 Similarly, the self-assembly of a collagen based PA can be stabilized by the inclusion of an alkyl tail to the peptide structure.81

The chain length of the tail as well as number of tails significantly affect the assembly of the PA. A model collagen peptide was used by Bianco-Peled group to study this effect.48 Interestingly, the single-tail and double-tail amphiphiles with C12 and C14 chains formed spheroidal micelles while increase in the tail length of the double-tail amphiphiles led to the formation of disk-like micelles that aggregated to form a strand like structure. The disklike micelles appeared as the transition structure between spheroidal micelles and bilayers. The disklike micelles are rare for single component systems and as mentioned by the authors, the formation mechanism for these unique aggregates is not clear. The


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cryo-TEM images are confirmed by SANS data analysis using sphere method. CD analyses showed that the peptide's ability to form triple helix can be affected by longer tail. Moreover, double-tail amphiphiles with C18 and C20 due to their crystalline nature disrupt the triple helix at room temperature which can be restored by increasing the temperature as the crystalline tails melt.

We have recently investigated the role of number of alkyl chains on the self-assembly of short peptide sequences.47 A series of PAs (17-23) were investigated for this purpose. The doubly lipidated PAs (17 - 19) promoted the -type structures like, twisted nanotapes/ribbons to helical fibrillar networks. Due to higher extent of hydrogen bonding among the head groups (KKK and KEK), higher ordered aggregation was observed in 17 and 18 as well as in their mixture. Interestingly, the single chain amphiphiles (19-23) failed to form any dominant aggregated morphology presumably because they failed to stabilize the -sheet structures as no negative cotton effect were observed at ~ 220 nm range for these amphiphiles. Presence of one more lipid group (17-19), enhanced the hydrogen bonding along the axial length resulting in much ordered aggregation. The solutions


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further formed hydrogel through hierarchical aggregation. The study shows the resultant effect of increased hydrophobic interactions and hydrogen bonding, which is also observed in the case of the co-assembly of the mixture of peptides (17+18).

The role of polar groups is an essential factor to be taken care of while designing a PA. For a typical lipidated PA, the overall charge on the head group sequence plays a crucial role towards the assembly process. The main role of the polar groups of an amphiphile is to provide solubility in water. For PAs, the solubility is in general a pH dependent phenomenon. The pKa of the free amine or acid groups of the PA thus plays a crucial role toward their aggregation. For instance, a peptide containing lysine as the polar residue, will remain soluble in acidic to neutral pH as the pI of lysine is ~ 9.7. If the pH of aqueous solution of the peptide is enhanced through addition of base, the solubility of the peptide decreases and hence the tendency of aggregation increases. Similarly, for an acid functional PA, initially it is dissolved at high pH and then the pH is adjusted to acidic range in order to form the aggregated structures. This pH controlled aggregation is a common tool for preparation of peptide based hydrogels. However, it is also noted that


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the aggregation pattern depends on the method of pH adjustment. A slow and kinetically controlled acidification via hydrolysis of lactones produces reproducible and uniform aggregated structures while sudden change through addition of acids leads to irreproducible results. Adams group have systematically showed the role of pH and control on pH change using several short peptide sequences.82-83 Hamley and coworkers reported the critical role of fine tuning of the pH of the medium for a lipidated PA, C16-KTTKS. The cationic PA formed various self-assembled structures at different pHs. The self-assembly structures were investigated at pH 2, 3, 4 and 7. A 1 wt% solution of the PA formed spherical micelles at pH 2 which changes to flat tape at pH 3 and twisted right handed structures at pH 4. Interestingly, upon increasing the pH to 7, the assembly transformed again to flat tape-like structures.84


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Figure 2. A) Schematic presentation of the thermodynamic and kinetic control of the selfassembly process of 28 in different solvent composition to show the formation mechanism of helical nano-fbers and nano-rings. B) Field emission scanning electron microscope


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(FESEM) images of the nano-structures formed by 28 in different solvents. Adapted with permission from Ahmed, S., et al. Sci. Rep. 2017, 7, 9485,59 and Ahmed, S., et al.

Langmuir 2018, 34, 8355-8364.60 Copyrights 2017 Springer Nature, and 2018 American Chemical Society.

Since the aggregation into ordered structures are driven by supramolecular interactions, it is essentially a thermodynamically controlled process. However, kinetics also play crucial role in structural modulation and function assimilation. A detailed account on the kinetic and thermodynamic aspects of the PA self-assemblies is recently published by Yan group.85 How the kinetic and thermodynamic parameters compete to control the aggregation process can be highlighted with the example of 28. Similar to the pH, the role of the solvent is extremely important toward the self-assembly process of PAs. An interesting morphogenesis was observed for 28 in different water-THF compositions. The PA was insoluble in water and thus the study was performed from 10% THF to 100% THF in water. In THF, right handed helical fibers were formed while in 10% THF-water, the aggregated structure changes to nano-rings along with a switch in the helicity to left-


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handed orientation (Figure 2).59 A combination of analytical studies and DFT calculations disclosed the involvement of thermodynamic and kinetic factors to control the selfaggregation process. In THF, the right handed helical fiber formation was governed by kinetic parameters. For 10% THF-water system, the nucleation process was controlled kinetically but owing to differential solubility of the molecule in these two solvents, elongation of the nuclei into fibers was restricted after a critical length and nano-rings were formed in a thermodynamically controlled fashion. The aggregation of the same PA was further studied in solvents of different polarity.60 The self-assembly and morphologies of the PDI containing peptide bola-amphiphile showed clear relation with the polarity of the solvent. Fiber-like morphology was observed in relatively nonpolar solvents (THF and CHCl3) whereas in more polar solvents, (HFIP, MeOH, ACN, and acetone) the PA formed spherical morphology (Figure 2). The aggregation was more efficient in polar solvents than in the nonpolar solvents. With decrease in solvent polarity, dimension of the nanostructures increased. Interestingly, irrespective of their polarity in all the tested solvents, the molecular aggregation adopted right-handed helicity.


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Introduction of aromatic amino acids to the sequences of PAs not only helps in aggregation but can also play crucial role in the aggregation pattern. Use of “FF” units in the peptide sequence is a common way to get self-aggregating peptides. A plethora of work has been carried out using this particular group.86-91 Amongst the natural amino acids, tryptophan is the only one that carries a fused aromatic ring. Das’ group have successfully utilized the  stacking of tryptophan in a single amino acid based lipidated PA.92 The cationic amphiphile could form helical fibrous network through effective involvement of hydrophobic interaction,  stacking of the indole ring of tryptophan, and hydrogen bonding. The PA could form a biocompatible hydrogel in water without the requirement of any pH adjustment. Another interesting study from the same group revealed that the minimum gelation concentration of similar cationic amphiphiles containing dipeptide at the head group decreases significantly with presence of more aromatic groups in the sequence.93


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Scheme 5. Schematic presentation of the self-assembly process of 26 under various conditions to form self-healing gels and use of aggregates of 26 for picric acid sensing. Adapted from Pramanik, B., Langmuir 2019, 35, 478-488,94 and Pramanik, B., ACS Appl.

Poylm. Mater. 2019, 1, 833-843.57 Copyrights 2019 American Chemical Society.

Presence of aromatic moiety as the hydrophobic group in PAs are also common. As discussed before, 26

contains lysine as the polar head group while, pyrene-butanoic

acid connected “FF” unit acts as the hydrophobic region.94 In water, 26 possibly forms


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micelle like aggregates which further go through higher order aggregation to produce disk like structures (Scheme 5). However, no hydrogel formation was observed even at a very high concentration. Interestingly, addition of a di-cationic NDI molecule (NDTA, Scheme 4) in equimolar ratio resulted in a self-supporting hydrogel. Detailed NOSY analyses revealed an unusual combination of cation- and charge transfer interaction between 26 and NDTA resulted into the hydrogel. It is interesting to note that, a portion of the pyrene ring is involved in the CT interaction with NDI while the other part of the group experiences cation- interaction with the cationic group of NDTA. Moreover, the two -planes adopted an angle of 56.07 ° between themselves. Such combination is very unusual and has never been reported before. Importantly, the same PA (26) forms a self-supporting hydrogel in 1:1 water-acetonitrile where the aggregation leads to well knitted fibrous network.57


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Scheme 6. Pictorial presentation of the hierarchical assembly of PAs.

Stepwise Assembly

The self-assembly of peptides in general follow hierarchical path as shown in Scheme 6.83 The aggregation happens in a concentration dependent fashion. At a diluted condition, two molecules come close to each other to form dimers. With increase in concentration, the dimers further assemble to get oligomers of the monomeric species. The aggregation further continues in parallel with the increasing concentration. At a particular concentration, smaller but of measureable size aggregates are generated.


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These aggregates could be micelles/vesicles (especially for PAs) or short and thin fibers/tapes. With further increase in concentration, these smaller aggregated structures get fused with other and start getting elongated in 1, 2, or 3 dimensions. The resultant nano-structures may further go through even higher order aggregation like nano-fibers, and get entangled with each other to form fibrous networks. The formation of network structures generally lead to entrapment of water molecules through cohesive forces resulting into hydrogels. Importantly, this stepwise assembly process was established via various supramolecular interactions.


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Scheme 7. Schematic presentation of the stepwise assembly of 24 in water to form hydrogel. Adapted from Singha, N., et al. Biomacromolecules 2017, 18, 3630-3641.55 Copyright 2017 American Chemical Society.

The hierarchical process can be understood with the example of 24. A three step aggregation process was observed for this particular PA which eventually forms a selfsupporting hydrogel above its critical gelation concentration (CGC).55 Combination of UVVis absorption, emission, and excitation spectra of the aqueous solution of 24 helped in identifying the minimum aggregation concentration 1 (MAC1) at ~ 0.05 mM (Scheme 7). At and above this concentration, the molecules started forming dimers through  stacking of the NDI groups. Another critical concentration was identified as MAC2 through DLS, emission spectroscopy, tensiometry, conductometry as well as Circular Dichroism (CD) techniques. Above MAC2, which is ~0.45 mM, the molecules assemble into spherical aggregates (presumably, micellar assemblies). FESEM and field emission transmission electron microscope (FETEM) images of sphere shaped structures of 50-60 nm diameter confirmed the presence of such aggregation. The spherical aggregates


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further assemble to form fibers which could be seen from the microscopic images. At 0.9 mM concentration, a combination of both spherical aggregates and nano-fibers were seen and above the CGC (16.9 mM), a fibrous network was obtained. Thus, the CGC can also be termed as MAC3.

PEPTIDE AMPHIPHILE BASED SOFT-MATERIALS

Hydrogel One of the most common final outcome of the self-assembly processes of PAs are the formation of hydrogels.14 As discussed in the previous section, the hierarchical assembly process of PAs often lead to a highly cross-linked network structure where water molecules get immobilized through cohesive forces resulting into a semi-solid selfsupporting hydrogel (Scheme 6). The tunable characteristics of hydrogels make them versatile and provide opportunities for specific applications. Peptide and PA based hydrogels have found tremendous attention especially in biomedical applications in recent past owing to their tunable, stimuli-responsive, and mostly biodegradable characters.20, 45, 95-97

Apart from biomedical applications, these hydrogels are often used for other


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purposes as well. During the process of evaluating the self-assembly processes of designer PAs, we have prepared several hydrogels out of these molecules and applied them for various applications.

Among the listed PAs in Scheme 2, 16-19,46-47 24,55 26,57, 94 and 2758 are some of the PAs which formed hydrogels. The self-aggregation mechanism of these hydrogelators were discussed at various points of this article. Importantly, combination of various supramolecular forces played crucial role in determining the aggregation pathway for all these molecules. For example, appropriate HLB is the key behind the hydrogelation of 17-19 while a combination of hydrophobic interaction, hydrogen bonding and  stacking lead to hydrogelation for 16. In case of 27, the hydrogel was formed through a combination of CT and cation- interaction. Moreover, the same molecule formed gel in 1:1 water-acetonitrile using only the -stacking and hydrogen bonding interactions. In case of 24, the  stacking between the NDI groups played the crucial role in the stepwise aggregation process.


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Figure 3. A) Photographs of a portion of the 1wt% hydrogel prepared from 27 and immerged in bulk water. Photographs taken at different times to show the insolubility of the hydrogel for a long time. B) Percentage dissolution of 1 wt% 27 hydrogel (20 mM Trisbuffer, pH 8) in different media after 168 h. Reproduced with permission from Singha, N., et al. Chem. Sci. 2019, 10, 5920-5928.58 Copyright 2019 Royal Society of Chemistry.

A unique hydrogel was formed by 27 in both water and Tris buffer (pH 8). Though prepared in water, the hydrogel did not get solubilized in water as well as many other aqueous or water-soluble organic medium for over a period of at least 18 months (Figure


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3).58 Importantly, any exchange of solute or solvent was found to be highly restricted across the hydrogel. Detailed dye exchange and NMR experiments showed that both water and dissolved dyes can get exchanged neither from the hydrogel nor from the outside bulk solvent for a long period of time. Importantly, the presence of pyrene as the hydrophobic residue plays a crucial role toward the formation of this particular aggregate. Compound 27, when dissolved in Tris buffer (pH 8) or in water, dimerizes through disulfide bond formation. The dimerization and aggregation of the dimer occur simultaneously to form a fibrous network where the water molecules get trapped. Very strong  stacking of the pyrene ring is one of the major reason behind the aggregation. Experimental studies along with molecular dynamic simulations revealed that 27 forms dimers through disulfide linkage which self-assemble into layers with a distinct 27-water interface. The stabilization of the hydrogel is a result of intra-molecular hydrogen bonds and the  stacking of the pyrene rings. The unusual confinement ability of the hydrogel is accredited to the slow dynamics of water which remain confined in the core region of 27 via hydrogen bonds. The confined water needs activation energies to move through water depleted


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hydrophobic environment of pyrene rings which significantly reduces water transport across the hydrogel.

Linear and Cross-Linked Polymers

Research in the domain of supramolecular polymeric materials has grown considerably in recent years due to their applications in sensing, drug delivery, and catalysis. In truesense, the well-ordered aggregation of small molecules using supramolecular forces can be considered as supramolecular polymerization. In these cases, the monomers polymerized through non-covalent interactions lead to growth of the polymer chain in one, two or even in three dimensions. The resultant structures thus are of various types like, fiber, tape, flake or brick-shaped etc. The supramolecular aggregation can also lead to cross-linked polymeric network. The network structures of physical gels are classic examples of such cross-linked polymers. Interestingly, most of these supramolecular polymers are having single monomer unit as in case of (A)n type homo-polymers. However, linear polymer that can grow in one direction and have alternate (AB)n type copolymeric arrangement are also reported using supramolecular aggregation process.


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One such example is the fibers obtained through CT interactions between 26 and NDTA (Scheme 5).94

Scheme 8. A) Redox controlled homo- and hetero-ternary complexation by CB[8] involving viologen as a guest. B) Schematic presentation of the formation and redox controlled reversible transformation of the supramolecular (AB)n type copolymer to an (A)n type homo-polymer using 31, PA – 32 and CB[8]. Adapted from ref Ahmed, S., et al.

Polym. Chem. 2016, 7, 4393-4401.98 Copyright 2015 Royal Society of Chemistry.


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The ternary complexation of CB[8] (Scheme 4A) is used to construct a (AB)n type linear supramolecular polymeric system using a simple bola-PA (32).98 A typical first guest for CB[8] is viologen while the second guests are in general electron rich fused aromatic rings like, naphthalene, pyrene or tryptophan. However, homo-ternary complexation is also feasible provided the guest fulfils all the required criteria. One electron reduction of viologen produces a viologen radical cation which can act as the guest for homo-ternary complexation as shown in Scheme 8. Using this phenomenon, a redox active supramolecular polymer was prepared where the reversible transformation of (AB)n type to (A)n type polymer could be achieved through a reversible redox reaction. The viologen dimer (31) and bola-PA (32), were used as two monomers of the polymer. The conjugation of these two monomers was achieved via the hetero-ternary complexation of Tryptophan residue and viologen unit inside the CB[8] cavity to form alternating copolymer of (AB)n type. The copolymer results in the formation of well dispersed microglobules (average diameter or 250 nm) and the calculated degree of polymerization (Dp) was ~128. Reducing the viologen units of the copolymer, viologen radical cations were formed in the solution which displaced the Trp units and formed complexes inside CB[8].


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This homo-ternary complexes eventually led to the formation of a homo-polymer of (A)n type. Dp was calculated to be much higher (328) than that of the copolymer, and larger micro-globules (∼950 nm) were obtained. The system reverted to the original co-polymer system upon oxidation of the homo-polymer. Several cycles of the reversible transformation can be achieved by controlling the redox reaction.

Another guest capable of forming homo-ternary complex with CB[8] is the FGG sequence of a peptide where the N-terminal is a free amine.99 A three way cross-linking strategy involving 33 was developed where the supramolecular cross-linking was achieved through CB[8] mediated homo-ternary complexation of the FGG units of the PA.100 The PA consists of three different cross-linking groups and a C-terminal RGDS sequence to provide cell-adhesion property of the cross-linked polymer (Figure 4). Covalent linkage through dithiol bond formation via the pendant thiol groups of Cys side chains, supramolecular linkage using CB[8], and biocatalytic dimerization of Tyr residues lead to the formation of the final cross-linked polymer decorated with RGDS sequence. The use of supramolecular cross-linking strategy in combination with covalent linking provides


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stability and brings the RGDS sequences at the surface of the polymer particles. Interestingly, the polymer size can be fine-tuned (200-1000 nm) by simple alteration of the order of cross-linking. The polymers obtained were very stable over a wide range of temperature and pH.

Figure 4. A) Chemical structure of the 33 and schematic presentation of the cross-linking strategies used to create three-way cross-linked polymers P1 and P2. B) FESEM images at different stages of the cross-linking of 33 following order A and B. Adapted from Dowari, P., et al. Biomacromolecules 2018, 19, 3994-4002.100 Copyright 2018 American Chemical Society.


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APPLICATIONS OF PA-BASED SOFT-MATERIALS

Applications of PA-assemblies are manifold. One of the biggest advantages of the PAbased self-assemblies over their covalent polymeric counterpart is their biocompatibility and biodegradability. In spite of several exceptions these natural amino acid based peptide systems are in general non-toxic in nature. These biologically relevant properties along with their mechanical and viscoelastic properties make them an attractive choice for various biomedical applications.20-21 However, the applications of these selfassembled systems are not restricted to biomaterials only. PA self-assemblies have found applications as chemo-sensors, in mineralization and template synthesis of nanomaterials, as conductive organic-electronic materials to name a few. In this section, we will discuss about some of the important applications of the soft-materials produced by the self-assembly of the PAs as mentioned earlier from our group.

Mineralization

Biomineralization of hydroxyapetite on cross-linked fibrils of 15 was first reported by Stupp’s group in their pioneering work on PA based soft materials.45,

101

Since then


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several reports have been surfaced where the nano-structures formed by the selfaggregation of PAs were used for direct mineralization to form composite materials. Mineralization of calcium phosphate was carried out in the hydrogels of PAs 17 and 18 using stepwise addition of calcium acetate and diammonium phosphate to the aqueous solutions of the PAs.47 Importantly, the addition of calcium acetate to the solution of 18 decreased the MGC significantly possibly due to the ionic cross-linkage between the calcium ions and the free carboxylate groups of the Glu residues. Addition of phosphate ions into calcium ion containing PA hydrogels resulted into calcium phosphate mineralization within the hydrogel matrix. The FESEM-energy-dispersive X-ray (EDX) analyses of the gel-fibers confirmed the mineralization at the surface of the fibers. The calcium phosphate mineralization technique is of particular interest as it is directly related to bone regeneration and dentistry.

Cell-Adhesion and Proliferation

Artificial extracellular matrix (ECM) is an essential component for tissue engineering and several peptide based soft-materials have been successfully tested for this purpose.30, 102


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One of the most important criteria for these self-assembled systems is that it must provide a surface where the cells can adhere. For linear peptide based systems, that can only be achieved through hierarchical supramolecular assembly to fibrous structures which can further entangle to form a network. In this regard, a cross-linked polymeric material with cell-adhesive units at the surface could be beneficial as the network is an integral part of the polymer. Use of cell-adhesive sequence, RGDS is a common approach while preparing soft materials for cell-adhesion and proliferation.38, 103-104 This particular aspect was testified with the multiple cross-linked polymer P1 and P2 (Figure 4). The presence of RGDS sequence at the C-terminal of the starting monomer helped the polymer particles to get a surface decorated with cell-adhesive ligand. As both the polymers were found non-toxic in nature, the materials were tested for cell adhesion using RAW 264.7 macrophage cells. Both the polymers can bind cells significantly. However, the extent of adhesion was found to be dose dependent for both polymers as the highest adhesion was obtained for 1280 μM. Moreover, polymer P2 showed better efficiency (6.4 times) than polymer P1 and that could be as a result of the order of cross-linking during the preparation of the polymer. It is also important to find out whether the adhered cells could


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proliferate on the surface and in the present case, the cells could proliferate significantly on both the polymer surfaces. A time dependent proliferation assay showed that 72 h incubation increased cellular proliferation by 52.4 ± 5% (for P1) and 33.5 ± 4% (for P2) on an average compared to 48 h incubated cells.

Intracellular Localization and pH sensing

The aggregation of NDI containing 24 showed clear dependence on the pH of the medium.55 The presence of one negative and two positively charged side chain functionalities affected the aggregation of the molecule in aqueous medium. The hydrogel formed by 24 became solution in presence of acid while the gel state remained unaffected in presence of base. Spectroscopic analysis revealed that under basic condition, the extent of aggregation was enhanced and the NDI core of the PA attains H-type aggregation at higher pH through stronger  interaction. As a consequence of the stronger -stacking, a broad peak centered at ~500 nm in the emission spectra of the PA became prominent at higher pH. This particular phenomenon was capitalized to use this PA for pH sensing inside cells (Figure 5). The presence of RGDS sequence at the C-


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terminal of the PA helped it to penetrate cell membrane and enter the cytosol. Inside the cell, the pH varies from one region/organelle to another and the appearance of strong emission band at ~500 nm at any particular region could be an indication of basic pH at that particular location inside the cell. To perform that, series of images were recorded within 400-600 nm range and each image was detected at a specific emission wavelength (lambda scan mode). Two different regions of interest (ROI) were selected at random and the emissions were recorded (Figure 5C). Images were taken at different emission wavelengths and the intensities against the wavelength. It was observed that at one region (ROI2), the band at 500 nm was much stronger than the other bands while in the other region, the intensity of that particular band was significantly lower. These observations indicate that, at ROI2, the PA aggregated strongly owing to a basic atmosphere and as a result, the band at ∼500 nm enhanced significantly. On the other hand, at ROI1, the lower intensity of the 500 nm band signifies neutral or lower pH. It is well established that mitochondrial matrix is alkaline in nature due to constant transport of proton to the inner membrane. To establish the fact that the PA can sense pH inside the cell, a colocalization study with MitoTracker (a fluorescent probe that labels


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mitochondria) was performed and the microscopic data revealed good correspondence between the luminiscence pattern of the PA and MitoTracker. These observations clearly suggests the potential of these materials to effectively probe intracellular pH.

Figure 5. A) Cell viability using MTT assay and (B) staining of RAW264.7 cells using 24 (blue). The cells were merged over bright field to ascertain intracellular localization. (C) Lambda scan images at the indicated wavelengths and (D) the corresponding emission intensity vs wavelength plots. Reproduced from Singha, N., et al. Biomacromolecules 2017, 18, 3630-3641.55 Copyright 2017 American Chemical Society.


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PA-Assembly as a Protective Envelop for Enzymes

The activity of a protein depends on its proper folding. Several supramolecular interactions are cleverly utilized by this group of biomolecules to get an optimum three dimensional structure. For an enzyme, the folding leads to create a reactive pocket where the substrate can bind and the chemical transformation takes place. Since the folding involves weak non-covalent interactions, any subtle change in the environment can cause damage to the structural integrity which is known as denaturation. Denaturation of enzymes lead to loss of their activity. Thus protecting enzymes from denaturing agents or effects is a real challenging task. A plethora of methodologies, including chemical modification, use of chaperons, immobilization on solid supports etc. have been applied to protect enzymes.105-107 The reported process in general suffers from low efficiency and also unable to provide a long life to proteins under antagonistic conditions. The unique confinement property of the hydrogel formed by PyKC (27) provided an excellent platform to protect enzymes from various denaturants for a long period (Figure 6).


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Figure 6. A) Graphical representation of the encapsulation of enzymes and prevention from denaturation in presence of different denaturing agents. Retention of the catalytic activities (%) of the gel-trapped and free enzymes (B) at different time intervals when incubated at room temperature, (C) as a function of temperature, (D) at different time intervals by the gel-trapped CR-lipase when dispersed in methanol or 6 M urea solutions. Reproduced with permission from Singha, N., et al. Chem. Sci. 2019, 10, 5920-5928.58 Copyright 2019 Royal Society of Chemistry.


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Since the hydrogel of PyKC does not allow any exchange of solute and water molecule and also has a tightly knitted network structure with pore size of ~ 3 nm, it was considered as an ideal candidate for this purpose. The hypothesis was that, once the enzymes are trapped inside the hydrogel network, a) no denaturing agent could get access to the enzymes as the gel does not allow any exchange of solute or solvent from the external environment, and b) because of the extremely small pore size, there will not be enough space for the trapped enzymes to unwind itself as a response of denaturing stimuli like, heat. Indeed, two different lipases were trapped in the PyKC hydrogel and subjected to solutions of various denaturing agents like, urea, methanol, and buffers of a wide range of pH (Figure 6). Notably, the enzymes could retain their activities (75-90%) under these conditions when subjected for a period of 7-30 days. Heating the samples at 70 °C for an hour also could not impart denaturation as ~ 80% activity was retained while under similar condition, the free enzymes completely lost their activity. Interestingly, the gel-trapped enzymes can be kept under ambient condition for a long period of time and remain active. The otherwise insoluble PyKC hydrogel can be re-dissolved in presence of any disulfide breaker like glutathione (GSH) or TCEP. Thus treatment of the hydrogels containing the


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trapped enzymes with these agents will allow one to release the enzymes and use it for any particular purpose. The system here opens up the possibility of easy storage and transport of biomolecules and needs to be explored further in future.

Figure 7. A) Pictorial presentation of the possible mechanism of silica nanotube formation. B) FESEM image of hydrogel of 16 in plain water (1% w/v) showing left-handed helical fibers. Inset: right handed helical fibers obtained from the D-analogue of 16 (1% w/v) in plain water. C) TEM and D) FESEM images of the silica nanotubes. Reproduced from Ahmed, S., et al. Langmuir 2013, 29, 14274-14283.46 Copyright 2013 American Chemical Society.


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Template for Hollow Silica Nanotube

The mineralization on the nano-structures created by PA self-assemblies is discussed earlier. For successful execution of mineralization, it is essential to create nano-structures decorated with a favorable functional group which allows the nucleation and growth of the inorganic materials on the surface of the nano-structures. Utilizing this nucleation-slow deposition-growth mechanism, silica nano-structures can also be created where the helical fibers formed by the self-assembly of 16 was used as the template (Figure 7).46 Tetraethoxysilane (TEOS), a well-established precursor for silica preparation, was mixed with the aqueous solution of 16.46 Initially, self-assembly of the PA leads to the fiber formation with free amines at the surface. The amine groups served as the nucleation point and a slow deposition of the TEOS molecules covered the entire surface. The amine group also served as the hydrolyzing agent for the deposited TEOS molecules which lead to the polymerization and consequently the silica formation. Upon calcination of this material, all the organic molecules from the template fibers were removed and resulted into the hollow silica nanotubes. The length and diameters of the SWNTs closely matches


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with that of the gel-fibers. However, attempts to add TEOS after the gel formation failed to produce the nano-tubes. Following similar approach, Dehsorkhi et al prepared sheetlike silica nano-tapes with striations using nano-tapes formed by C16-KTTKS peptide as template.108

PA-Assemblies as Chemo-Sensors

A chemo-sensor is a chemical system/molecule that is used for the detection of an analyte to produce easily detectable responses upon interaction with the analyte. Among the different chemo-sensors, fluorescent active sensors have emerged as an attractive domain because of their high sensitivity, ease of operation, applicability in different material states, real-time detection, non-destructive determination and low-cost instrumentation. In this regard, ADIs have emerged as efficient fluorescent sensors especially owing to their high photochemical stability and high quantum yields. Importantly, the fluorescence efficiency and pattern of these systems can easily be finetuned through their aggregation behavior. The aggregation-disaggregation of these ADIs


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has been effectively utilized to develop several efficient sensors for a variety of analytes.109-112

Figure 8. A) Schematic presentation of the mechanism of tandem sensing of Pd2+ and CN- through assembly-disassembly of 25. B) Photographs of solutions of 25 in presence


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of different metal ions; Top: under normal light and Bottom: under UV light, [25] = 1 × 10-6 M; C) Photographs of solutions of 2:1 complex of 25 and Pd2+ in presence of different anions; top: under normal light and bottom: under UV light, [25] = 1 × 10-6 M. Reproduced from Pramanik, B., et al. ChemistrySelect 2017, 2, 10061-10066.56 Copyright 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A peptide amphiphile (25) was designed by incorporating PDI group in between a short pyridine functionalized peptide sequence and a hydrophobic tail.56 The idea behind this designer PA was that the pyridine groups of the peptide will act as a ligand to bind metal ions and consequently affect the aggregation of the PDI group providing a fluorescence response towards the metal ion (Figure 8A). In presence of Pd2+ ions, two of these molecules bind to the metal ion and consequently leads to aggregation of the molecule via  stacking of the PDI groups. The study was performed at concentration of the PA where no aggregation was observed in absence of Pd2+ ions. The aggregation resulted in a significant decrease in the emission intensity which was quantified with respect to the metal ion concentration (Figure 8B). The “turn-off” sensing of Pd2+ ions by 25 showed a


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detection limit of 0.55 ppb which is much lower than similar chemosensors reported. Interestingly, the palladium complex was further utilized for tandem sensing of CN- ions where the complex acted as a “turn-on” sensor. Since CN- ions have strong affinity toward Pd2+ ions, addition of cyanide salts to the Palladium complex solution of 25 leads to the formation of [Pd(CN)4]2- complexes which results in dis-assembly of the ligand and the fluorescence jumped back to its initial non-aggregated-state emission (Figure 8C). The detection limit for CN- was calculated to be 0.26 ppb. Both, palladium and cyanide sensing by 25 was found to be extremely selective and effective toward environmental samples like tap or pond water. A thin layer chromatography (TLC) plate based tandem detection of Pd2+ and CN- was also prepared out of this PA (Figure 8D).

Another important fluorophore commonly used for chemosensor development is pyrene. This fused aromatic system shows excellent environment dependent emission property. Moreover, -stacking induced excimer formation by pyrene is a great tool for chemists to design and construct sensing materials. Dimerization of pyrene generates a new broad band in its emission profile at ~500 nm. Any analyte that induces the formation or


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destruction of the excimer could be detected using pyrene conjugated sensors. Being highly electron rich, pyrene has a tendency to bind with nitro-phenols which breaks the excimer and thereby results in a quenching of the excimer band. Following this principle, 27 was designed where the FFK peptide sequence helps in forming -sheet like aggregates and favors the formation of pyrene excimers by bringing the pyrene rings to a close proximity (Scheme 4). The PA forms an efficient hydrogel in water with MGC of 21.85 mM. The PA is capable of selectively sensing picric acid, a well-known explosive, in both sol and gel conditions. Interestingly, in gel state, the sensing depends on the excimer band of pyrene but the detection of picric acid in sol state entirely depends on the monomer emission of pyrene. In sol state, the PA molecules remain in nonaggregated state and upon addition of nitrophenols, complexation between the nitrophenol and pyrene leads to a sharp decrease in the monomer emission intensity. In gel state, the aggregation is so strong that only the excimer emission is obtained and presence of nitrophenols actually breaks these excimers to find a place between two pyrene rings within the stacks. As a result, the excimer emission drops significantly which can be quantified. In both sol and gel state, the system showed high selectivity toward


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picric acid amongst a variety of aromatic compounds. The method was further extended to gel coated paper strip for a useful and practical method of picric acid detection. Notably, the detection limit for the paper based system was in the order of femtogram which shows the high efficiency of the sensor.

Application in Organic Semiconductors

Arylene mono and diimides are well-known as n-type organic semiconductors and several studies have been so far carried out to understand their conducting properties as well as their use in organic-electronic devices.113-115 Our group is involved in fundamental understanding on the effect of self-aggregation process on the semiconducting properties on ADI-conjugated PAs. As mentioned earlier, 28 forms different nano-structures in different solvents. A detailed conductometric study of these nano-structures showed a clear relation between the conducting property and the morphology. It was observed that 28 has a tendency to form spherical aggregates in polar solvents while in apolar solvents the aggregation leads to long fiber like structure (Figure 2).59-60 For example, nano-cup like structures were obtained in methanol and in hexafluoroisopropanol it formed nano-


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spheres. Similarly, in a non-polar solvent like THF, the morphology was of helical nanofibers. Detailed conductometric analyses of these nano-structures revealed that the conductance of the fibrous morphologies were much higher than that of the spherical or ring like structures. A realistic correlation is only possible when several such systems are studied in detail. Our group is in the process of studying some more similar type of systems involving both, NDI and PDI based PAs and hopefully, these results will provide enough information to create new systems with desired conducting properties. In addition, using these conducting PAs, we have already prepared a device capable of sensing pxylene selectively at room temperature and the results will be reported in due course of time. These results will certainly generate possibilities of using these conjugated PAs for further applications in organic electronic devices.


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Table 1. Nano-structures formed by different PAs and their applications.

PA

Medium/Solvent/Condition

Nano-structure

Application

Ref

3

PBS (pH 7.4)

Membrane (nano-fiber)

-

31

4

Basic pH

Scaffold nanostructure

-

32

5-8

PBS buffer

Nano-vesicles

Drug delivery

29

8-14

Below pI

Nanotubes and nanovesicles

-

36

Above pI

large membranous sheets

15

pH 8

Nano-fiber

Hydroxyapetite mineralization

45

16

Water

Helical nano-fiber (hydrogel)

Nano-fabrication

46

17

Water

Helical Nano-fiber

Mineralization

47

18

Water

Helical Nano-fiber

Mineralization

47

19

Water

Twisted nano-tape

-

47

24

Water

Nano

sphere

(at

lower Intracellular pH sensing

55

concentration) Nano-fiber (at higher concentration) 25

1:2 DMF-water

Spherical Aggregates

Tandem sensing of Pd2+ and 56 CN-

26

1:1 water-ACN

Fibrous network (Gel)

Picric acid sensing

57

Water + NDTA

Nano-flakes (Hydrogel)

-

94

27

Tris buffer (pH 8)

Fibrous network (Hydrogel)

Protection of Enzymes

58

28

10% water-THF

Nano-ring

Organic electronic

59


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THF

Nano-fiber

59,60

Chloroform

Nano-fiber

60

Acetone

Nano-sphere

60

Acetonitrile

Nano-sphere

60

Methanol

Nano-cup

60

HFIP

Nano-sphere

60

29 or 30

Water (CB[8] and viologen amphiphile)

Vesicle

Drug delivery

77, 78

31

Water + CB[8] + 32

Nano-sphere (Polymer)

Redox active polymer

98

33

Water + CB[8] + H2O2

Nano-sphere (Polymer)

Cell

adhesion

and 100

proliferation KTVIIE

Glycine-HCl buffer (pH 2.5)

Nano-fibers

-

80

C16KTTKS

pH2

Spherical micelle

Cosmetics

84

pH3

Multilayered flat-tape

pH4

Twisted fibril

pH7

Flat-tape


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CONCLUSION AND FUTURE PERSPECTIVE Table1 exhibits the structure of all the PAs discussed in this article, in order to establish a correspondence between different nano-structures formed by them under variable conditions and their application in numerous fields. This article describes and discourses most of our published work on designer PAs pertaining to their design, mechanism of self-assembly and further their applications. Design and synthesis of these molecules have always been executed with the objective towards targeted applications. The self-assembly of PAs are mainly thermodynamically controlled as they majorly comprise of various non-covalent interactions. However, depending on the environment, they are at times kinetically driven and conclusively determine the final nano-structures. Temperature, pH, solvent etc. can radically change the self-assembly pattern. Thus, it is important to understand the prerequisites of a particular application and design the PA accordingly keeping in mind the possible effect of the various determining parameters. The last three decades have witnessed a thriving effort towards understanding the mechanistic pathway of self-assembly of the PA based systems. The knowledge derived from this enormous literature alleviated the pathway to


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design of peptide amphiphiles for targeted applications. We believe, it is time to utilize this knowledge to create newer and more promising self-assemblies having higher efficacy in desired fields. Some such highly potential self-assembled systems are imminent while many new ones to be buoyantly found in future. Though not to forget that even with this voluminous work on self-assemblies, supramolecular chemistry never fails to create surprises. Systems with unique properties and newer aggregation mechanism are reported recurrently. Thus it still remains equally important to understand these new systems as coherently as have been done so far.

AUTHOR INFORMATION

Corresponding Author * [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.


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ACKNOWLEDGMENT DD acknowledges financial support from SERB (EMR/2016/000857), India, UKIERI (DST/INT/UK/P-119/2016), the Alexander von Humboldt Foundation, Germany, and the DSTFIST program. Dedication

To our mentor, Professor Prasanta Kumar Das, IACS, Kolkata. REFERENCES (1) Draper, E. R.; Adams, D. J. Low-Molecular-Weight Gels: The State of the Art. Chem 2017, 3, 390-410.

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Table of Content Graphic


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BIOGRAPHIES

Dr. Antara Dasgupta completed her PhD under the guidance of Prof. P. K. Das from IACS, Kolkata, India in 2008. Then she joined Prof. Thayumanavan’s group at University of Massachusetts, Amherst as a postdoctoral researcher. In 2009, she moved to University of Duisburg, Essen, Germany to join Prof. T. Schradder as an Alexander von Humboldt fellow. After her postdoctoral research, she joined Galgotia’s University, India as an Assistant Professor where she worked till 2012. Then she joined Department of Chemistry, Indian Institute of Technology as a principal Investigator and worked in the area of Peptide Amphiphiles and their self-assemblies. Dr. Dasgupta is currently working as an assistant manager at Eris Lifesciences. Her research interest include peptide based soft materials.

Dr. Debapratim Das did his doctoral research under the guidance of Prof. P. K. Das from IACS, Kolkata, India. In 2007, he joined Prof. Herbert Waldmann at MPI Dortmund,


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Germany as an Alexander von Humboldt fellow and worked there till 2009. Thereafter he moved to University of Cambridge, UK to work with Prof. Oren Scherman. In 2011, he joined Department of Chemistry, Indian Institute of Technology as an assistant professor. Since 2015, he is working as an associate professor in the same department. Dr. Das’ research focused on supramolecular dynamic aggregates of small peptides.


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Designer Peptide Amphiphiles - American Chemical Society

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