Synthetic Catalysts Inspired by Hydrolytic Enzymes - ACS Catalysis

Oct 30, 2018 - Kahne, D.; Still, W. C. Hydrolysis of a Peptide Bond in Neutral Water. ...... Amino Acids 2008, 35, 251– 256, DOI: 10.1007/s00726-007...
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Synthetic Catalysts Inspired by Hydrolytic Enzymes Mitchell D. Nothling, Zeyun Xiao, Ayana Bhaskaran, Mitchell Tabrum Blyth, Christopher Bennett, Michelle L. Coote, and Luke A. Connal ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03326 • Publication Date (Web): 30 Oct 2018 Downloaded from http://pubs.acs.org on October 30, 2018

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Synthetic Catalysts Inspired by Hydrolytic Enzymes Mitchell D. Nothling,†[a] Zeyun Xiao,†[b] Ayana Bhaskaran,[c] Mitchell T. Blyth,[c] Christopher Bennett,[c] Michelle L. Coote,[c] and Luke A. Connal*[c] Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia [b] Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, P. R. China [c] Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia [a]

ABSTRACT: Enzymes, as nature’s catalysts, speed up the very reactions that make life possible. Hydrolytic enzymes are a particularly important enzyme class responsible for the catalytic breakdown of lipids, starches and proteins in nature, and displaying increasing industrial relevance. While the unrivalled catalytic effect of enzymes continues to be unmatched by synthetic systems, recent progress has been made in the design of hydrolase-inspired catalysts by imitating and incorporating specific features observed in native enzyme protein structures. The development of such enzyme-inspired materials holds promise for more robust and industrially relevant alternatives to enzymatic catalysis, as well as deeper insights into the function of native enzymes. This review will explore recent research in the development of synthetic catalysts based on the chemistry of hydrolytic enzymes. A focus on the key aspects of hydrolytic enzyme structure and catalytic mechanism will be explored – including active-site chemistry, tuning transition-state interactions, and establishing reactive nanoenvironments conducive to attracting, binding and releasing target molecules. A key focus is to highlight the progress toward an effective, versatile hydrolase-inspired catalyst by incorporating the molecular design principles laid down by nature. KEYWORDS: Hydrolytic enzyme, enzyme mimic, catalyst, catalytic triad, reaction mechanism

1. INTRODUCTION

has resulted in an accelerating volume of research to explore new avenues for exploiting hydrolases.4-8

Hydrolytic enzymes (hydrolases) are a class of more than 200 individual proteins that catalyze the hydrolysis of a range of unique chemical bonds.1-3 Several divergent hydrolase families have been developed by nature, including proteases, lipases, nucleases, and amylases, each with a distinct biochemical role.3 While the specific protein structure and catalytic mechanism vary, the overall hydrolytic reaction can be summarized as follows: A–B + H2O → A–OH + B–H Due to their versatility, frequent promiscuity and industrially significant chemical transformations, hydrolases as an enzyme class find outstanding relevance in commercial applications, ranging from laundry powder and biomass conversion, to chemical weapon degradation and fine chemical production. In addition, the mild nature of hydrolase-catalyzed reactions, paired with the modern focus on ‘green’ chemical procedures,

One of the most representative hydrolase families is the proteases, which degrade proteins in nature by breaking down the peptide (amide) bonds that link amino acids.9-10 Similar to many physiochemical processes, the breakdown of peptide bonds occurs slowly (of the order of several years) in the absence of a protease at neutral pH and ambient temperature, despite the reaction being thermodynamically favorable.11 In contrast, proteases accelerate the breakdown of amide bonds 109–1011-fold faster than the non-enzymatic reaction, approaching a diffusion-limited reaction rate.12 Like all enzymes, the key to protease activity lies in the specific folded tertiary structure of the parent protein, whereby remote amino acid residues along the protein backbone are brought into close proximity by protein folding. The spontaneous process of protein folding is guided by a suite of interactions, including intramolecular hydrogen-bonding and van der Waals forces, as

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well as hydrophobic interactions.13 However, while the evolutionary development of the specific protein folding in enzymes has resulted in their unrivalled catalytic effect, this network is easily disturbed by environmental stresses, such as temperature, salt concentration, pH, organic solvents and even the presence of other enzymes.14 When taken in combination, these factors greatly limit the application of enzymes in industry, where reaction environments are seldom as finely controlled as that of biological systems. A long-standing challenge in catalyst design has been to develop simple synthetic systems that can perform bio-inspired chemistry, without the need for well-defined tertiary structures, and at the same time overcoming the operating window limitations of natural enzymes. An understanding that enzymes are “not different, just better” has been a guiding mantra for organic chemists looking to model these remarkable biomacromolecules.15-16 To approach this challenge, pioneering work by Breslow and others developed a range of strategies in the general area of enzyme mimicry.17-18 Examples of bioinspired catalysis include metal-based active sites, polymeric, peptidic, and dendritic supports, as well as catalytic dyads.19-26 However, the design and performance of synthetic catalysts that mimic hydrolytic enzymes in both range and efficiency of chemical transformations continues to be a major challenge. 27-

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different protease families, a number of key aspects are common:35-36 - The active site - specific functional groups that perform catalysis via covalent interaction with the substrate,37 brought into proximity by the folding of the enzyme protein. Represented by the common active site example of an acidbase-nucleophile triad, known as the ‘catalytic triad’ (Figure 1).38-39 The Ser-His-Asp motif is one of the most thoroughly characterized and well-understood catalytic triads, however Cys-His-Asp, Ser-His-His, and Ser-Glu-Asp are also found in natural hydrolytic enzymes.40

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Several reviews have been published summarizing enzyme mimics.19-25, 27 However, there is has been no review specifically dealing with mimicry of the large and important hydrolase enzyme class. This review will explore the research to date in the development of synthetic catalysts based on the chemistry of hydrolytic enzymes. It will begin with an introduction on the representative structure of some hydrolases, with a particular focus on the illustrative and industrially useful proteases. A focus on the key links between structure and mechanism will be explored, highlighting the design principles that must be addressed by researchers in the development of effective protease mimics. As a major component of this review, a particular focus is given to the development of strategies to mimic the ubiquitous ‘catalytic triad’ active site chemistry of proteases. The creation of simpler organic compounds that mimic the working features of hydrolytic enzymes is a formidable task, but progress in this direction has been steadily increasing. This review will focus on how past studies into the structure and function of hydrolytic enzymes have guided the development of an enzyme-inspired catalyst, and what remains to be done to realize a truly enzyme-mimetic catalyst.

2. Hydrolytic Enzymes: Structure, Catalytic Reactions and Mechanism A biologically important and well-studied class of hydrolase enzyme are the serine proteases.12, 32-33 Their occurrence in nature is widespread, playing a pivotal role in many normal human and disease-related functions.33 Serine proteases are relatively simple enzymes to isolate, crystalize and study, having been well researched since the late 1930s.34 The serine proteases occur as a single protein unit with a single active site, which do not utilize a co-factor to support their proteolytic action. While specific structural elements vary between the

Figure 1. Protein structure of α-chymotrypsin, a well-studied and illustrative serine protease highlighting the active site residues composed of the Ser-His-Asp “catalytic triad”.

- Binding pocket - the region surrounding the active site that can attract, partition and align certain substrates, as well as facilitate ejection of reaction products. In chymotrypsin-like hydrolases, this pocket is a hydrophobic region. - Substrate recognition - orientation of core functional groups (‘lock’) that accepts substrates of a particular shape/size (‘key’) via an induced fit, thereby defining the highly specific target structures of the parent enzyme.41-43 - Transition state binding - a covalent interaction between the substrate transition states during catalysis, and residues near the active site that reduce the activation energy for transition state formation. In addition, supporting H-bonding and directional electric fields in the active site arising from charged residues are also known to contribute to transition state stabilisation.44-45 Although the individual impact of each of these structural features is modest in isolation, the aggregate effect adds to be significant and is responsible for the unrivalled catalytic reactions afforded by the hydrolases. Many of these structural features were first defined for -chymotrypsin, the most widely studied and best-understood of the serine proteases, and the first to be isolated.46 Chymotrypsin is an important digestive enzyme in mammals. It is produced by the pancreas and exerts its activity in the small intestine, along with the related enzymes trypsin and elastase. Characterization of chymotrypsin’s mechanism was first studied by Dixon & Neurath in 1956 using the nerve gas diisopropyl fluorophosphate (DFP) as an affinity labelling inhibitor.47 They established that a single serine residue (Ser195) was important for the action of chymotrypsin,

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which was later recognized as a defining feature of the serine proteases. Further inhibitory studies by Schoellmann and Shaw in 1963 and X-ray crystallographic work by Blow et al. in 1969 established the presence of a ‘catalytic triad’ of serine, histidine and aspartate residues at the active site.48-49 As to the catalytic mechanism, interactions between functional residues of the catalytic triad perform the actual attack of the substrate amide bond and subsequent hydrolysis.49-50 More specifically, the Asp carbonyl is hydrogen bonded with the imidazole ring of His, increasing the pKa of the imidazole nitrogen and resulting in it acting as a strong general base. The imidazole nitrogen deprotonates the alcohol group of the Ser residue, creating a powerful nucleophile for attack on the scissile amide carbonyl of the substrate (Figure 2). Backbone amide groups in the protein act to delocalize the charge of the anionic tetrahedral intermediate and reduce the activation energy of the transition state, a key stage of catalysis. In addition, electrostatic stabilization via interaction of the charged intermediate with the electric fields of nearby charged residues (such as Asp carboxylate groups) plays a considerable role in reducing the activation energy of the transition state.36, 44 Following acylation of the Ser hydroxyl, a further substitutionelimination reaction occurs whereby water from solution acts as a nucleophile, and the His imidazole acts as a general acid, to regenerate the catalyst and eliminate the terminal amide product (Figure 2). This mechanism, and the catalytic triad motif in general, is a result of the specific, folded tertiary structure of the parent protein, and has now been observed to occur in some form in over 300 different enzymes.51 In addition, the participation of just a small number of proximal and suitably aligned residues at the enzyme’s active site is a feature that is common across the majority of enzyme families in general.

Figure 2. General reaction mechanism of hydrolysis of an amide substrate (blue/red) catalyzed by a protease Ser-His-Asp catalytic triad (black) (dashed lines represent hydrogenbonding). Activation of the Ser hydroxyl unit by interaction with the His imidazole forms a strong nucleophile for attack on the scissile carbonyl of the substrate, resulting in a covalently attached acyl-enzyme intermediate and ejecting the amine product. Subsequent hydrolysis by H2O ejects the acid product and regenerates the catalytic triad. An ‘oxyanion hole’ (green) of nearby peptide N–H bonds plays a key supporting role in

catalysis, reducing the activation energy of the charged tetrahedral transition states. While the catalytic triad is responsible for the proteolytic reaction performed by the serine proteases, additional nearby amino acid residues serve key roles in attracting, binding and supporting the substrate as the catalysis progresses. Backbone amide groups in the protein act as an ‘oxyanion hole’ that delocalizes the charge of the tetrahedral intermediate by forming short hydrogen bonds with the charged species as it forms.52 This stabilization reduces the activation energy of forming the charged transition state, and is a key stage of catalysis. Single glycine and serine residues have been identified as the key constituents of the oxyanion hole in chymotrypsin, though a similar role is performed by aspartate and arginine residues in other proteases.36 The lock and key mechanism introduced by Fischer highlights this phenomenon well, whereby the well-defined alignment of amino acid residues (the lock) facilitates the essential electrostatic interaction between enzyme and substrate (the key).41-42 The idea of an optimally shaped binding pocket was expanded on by Koshland in his seminal paper outlining the idea of an ‘induced fit’, where the dynamic binding pocket residues can adapt to suit the electrostatic environments of the changing transition states – more “hand-in-glove” than “key-in-lock”.43, 53 While the active site and oxyanion hole are the main structural elements that afford catalysis, attracting and partitioning substrates toward the active site is first essential. Similar to the oxyanion hole, amino acid residues surrounding the catalytic triad establish an internal environment within the enzyme that only permits certain types of substrates to enter. This region is known as the substrate binding-pocket and forms the basis of the very high level of specificity of enzymes in general.30, 54 In chymotrypsin-like hydrolases, the binding pocket is composed of hydrophobic residues, such as tyrosine, tryptophan, and phenylalanine, which create a preference for hydrophobic substrate residues. Similarly, the binding pocket of trypsin-like proteases is composed of negatively charged residues, such as aspartate or glutamate, and will preferentially react with positively charged substrate residues.50 The binding pocket also serves to align the incoming substrate for optimized attack by the catalytic triad. This attraction and orientation of substrates aids the catalytic mechanism of the active site and defines the operating window of the parent enzyme. This is highlighted by examples of immune-response proteases responsible for cleaving a single protein at a specific amide bond, a considerable feat that represents a grand challenge for modern synthetic chemists.

3. Mimicking Hydrolytic Enzymes The key aspects of enzyme structure and mechanism discussed so far have been used as design criteria for producing synthetic enzyme mimics.19-20, 55-57 The goal of these materials is to afford a catalytic effect in a similar manner to the natural enzyme. The following sections of this review will explore how past studies have aimed to mimic one or more of the key structural features of hydrolytic enzymes in a bio-inspired catalytic material. These structural features are the active site, the oxyanion hole for transition state stabilization, and the hydrophobic binding pocket, as well as rational combinations of these structural

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features. The field of metal centred hydrolytic enzyme mimics has been summarized by Scrimin et al and thus will lie outside of the scope of this review.58 Instead, the key focus of this analysis is to give a perspective of work to date with acid-basenucleophile enzyme mimics. In particular, the hydrolaseinspired catalytic systems that employ important structural aspects of the serine proteases to deliver hydrolytic catalysis will be explored.

3.1 The Active Site As the functional core of an enzyme, the chemistry of the active site provides excellent inspiration for researchers looking to design a catalyst that can mimic the performance of enzymes. The catalytic residues of the active site directly participate in the hydrolytic reaction of interest;37 however, it is the precise alignment and local environment surrounding the active site that gives rise to the remarkable catalysis that is observed for these materials. Thus, the simple combination of acid-basenucleophile units would be expected to exhibit limited effectiveness for hydrolytic catalysis in isolation. Despite this, the active site chemistry is an attractive and well-understood component of enzyme catalysis and a number of past studies have tried to replicate these structural features, especially for mimicking the catalytic triad.59-61

Figure 3. The dipeptide Ser-His mimicking the catalytic triad. Seri-His was first reported to catalyze ester, amide and protein hydrolysis in 2000 (model ester substrate shown, p-nitrophenyl acetate (p-NPAc)), but the claim was opposed by others in a recent study.61-62 Chen et al. reported in 2000 that the simple dipeptide SerineHistidine (Ser-His) is capable of undertaking esterolytic, proteolytic and DNA cleavage reactions.61 Ser-His essentially contains the three functional groups of the catalytic triad positioned within close proximity on the same molecule and has been suggested by Chen as a potential protease model (Figure 3). Follow-up experimental and modelling studies by the same group into the hydrolytic and peptide condensation activity of the Ser-His protease-mimic has consolidated the surprising versatility of the dipeptide for undertaking enzyme-like hydrolytic reactions.63-65 However, subsequent studies suggest that the Ser-His dipeptide is not sufficient by itself to catalyze more challenging amidolysis and proteolysis reactions.62 This finding seems to be supported by a series of elegant studies by Szostak et al. employing the Ser-His dipeptide as peptide condensation and non-enzymatic RNA replication catalysts in a prebiotic, origin of life scenario.66-69 In these studies, the condensation activity of Ser-His is minimal when observed in isolation but becomes significantly enhanced when the dipeptide is incorporated into fatty acid vesicles as models of a protocell membrane. This implies that the Ser-His moiety requires localization in a

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hydrophobic environment to develop catalytic activity, which is indeed the environment of this moiety in the active site of proteases. The use of computation in both natural and mimicry systems provides a powerful tool to understand the mechanism of catalysis and gives clues to optimize mimic design. In a combined computational–experimental study, the catalysis of Michael-type addition of thiols was carried out for a wild-type lipase and a redesigned mutant lipase that lacked the nucleophilic Ser105 residue in the active site.70 Using quantummechanic (QM) calculations, the mutant was studied in a model system designed to mimic the catalytic properties of the active site, aligning closely with their experimental findings. Computational design of active sites is a promising area of research that may help to understand the mechanisms of natural enzymes and to implement these when designing small molecule enzyme-mimics.71 3.2 The Binding Pocket and Transition State Stabilization As its core role, a catalyst lowers the activation energy of a reaction, allowing otherwise kinetically unfavorable reactions to proceed through to product formation. In enzymes, supporting residues nearby to the enzyme’s active site help to perform the task of lowering the energy of the transition state(s) between the bound substrate and released products.72 A multitude of covalent, orbital and electrostatic interactions are established around the active site to support TS stabilization, driven by the enforced proximity of multiple functional groups.73-74 A key mechanism by which this is achieved is through hydrogen bonding.75 In hydrolytic enzymes, specific amine and amide residues perform this function in order to withdraw electron density from the charged intermediate via the formation of short enzyme–substrate hydrogen bonds. More specifically, for chymotrypsin-like hydrolytic enzymes, the key transition state is a tetrahedral anionic species, covalently bound to the enzyme’s serine hydroxyl residue, and stabilized by nearby serine and glycine amine residues (Figure 4).26 These supporting residues are appropriately aligned to interact with the bound substrate in a way that complements the action of the enzyme’s active site residues. Furthermore, these residues are not static but display significant “mobility” in orientation around the TS binding pocket, dynamically adapting in recognition of the changes in electrostatic density as the reaction progresses.53, 76 As early as the 1970s, Warshel proposed that it is this strong electrostatic stabilization within enzymes that contributes primarily to enzymatic catalysis.77-78 That is, the various charged residues within the enzyme active site generate a directional electric field that is capable of stabilizing polar transition states, and thus lowering reaction barriers. These electrostatic interactions are complementary to orbital interactions and are greatest when the polarity is low, as is typical of many active sites. Shaik and co-workers went a step further and showed in simulations that an applied electric field could be used to mimic the catalytic power of cytochrome P450.79 While this pioneering work was based on theoretical calculations, in 2014 Boxer and co-workers used Stark spectroscopy to provide experimental evidence of strong electric fields within enzyme active sites. In parallel to this, experimental evidence that electrostatic effects, from either

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charged functional groups80-81 or external electric fields,82-83 can be responsible for chemical catalysis was provided by Coote and co-workers, illustrating experimental proof of concept. Transition state stabilization has received a significant volume of attention from synthetic chemists looking to harness this catalytic effect, with transition state analogues and hydrogen bond catalysis both widely explored techniques in this field.26 This review will not attempt to exhaustively survey the substantial literature in organic catalysis via transition state stabilization, rather a few recent and illustrative examples will be shown here. The interested reader is directed to a number of excellent reviews on hydrogen-bond catalysis,84-86 electrostatic effects in enzyme catalysis,87-88 transition state analogues and molecularly imprinted polymers (MIPs).89-91

Nevertheless, numerous macrocyles have been synthesized for the purpose of mimicking the binding pocket of enzymes, and further discussion on this this active area of research is undertaken later in this review.98-104 A recent example is reported by Sessler et al. describing a large capsule-like biscalix[4]pyrrole, which is able to host two dihydrogen phosphate anions concurrently within a relatively large internal cavity (Figure 5).105-106 The ubiquity of related complexation events in the context of enzymatic transformations leads them to propose that systems such as these could serve as useful structural enzyme models, which may help increase our understanding of natural oxyanion recognition processes.

Figure 5. A Bis-calix[4]pyrrole mimicking the oxyanion hole. The large capsule-like biscalix[4]pyrrole molecule is able to concurrently host two dihydrogen phosphate anions through hydrogen bonding, similar to the enzymatic binding cavity. Reprinted with permission from ref 106. Copyright 2017, American Chemical Society.

Figure 4. Transition State Stabilization. The concerted effort between the catalytic triad and the double hydrogen bond donating oxyanion hole, initiates the catalytic reaction, and stabilizes the charged transition state in -chymotrypsin.26 Expanding on the early ideas proposed by Pauling of enzymetransition state interactions, Cram and Lehn made some of the earliest progress on the synthesis of artificial active sites by targeting mimicry of the enzyme’s internal environment.92-94 Their work, recognized by the 1987 Nobel Prize in chemistry shared with Pederson, introduced the concept of host-guest chemistry, whereby the functional groups of the enzyme, and therefore the mimic, are convergent to create a particularly shaped host cavity for receipt of the substrate. While this work did not specifically target the mimicry of enzymatic catalysis, the field of host-guest chemistry has provided valuable insights to the performance of enzymes and the design of enzymeinspired systems. Cram explored crown ether macrocyles, which could incrementally mimic some of the stereo–, regio– and functional group specificity displayed by enzymes.95 Key to this approach, later expanded by Breslow,96 was the preorganized and rigid structure afforded by the macrocycle, which could specifically target binding of substrate and transition state conformations. Issues have been raised however, as to whether these systems truly perform catalysis owing to the stoichiometric concentration of mimic required, with possible irreversible binding of intermediates.97 Furthermore, the dynamic nature of transition state binding nicely discussed by Kirby introduces an additional layer of complexity that would be very difficult to realize with these rigid cyclic systems.53

Transition state analogues (TSAs) have been widely explored as enzyme mimics by medicinal chemists and biochemists, exploiting the strong interaction of the enzyme binding pocket with the transition state structure.57, 107 A number of modern drugs employ a transition state-mimicking structure to block the action of enzymes associated with viral and bacterial infections including, asthma, gout and acute pain, amongst many other diseases.108 In the design of enzyme-mimicking catalysts, a transition state analogue can be used to build a surrounding molecule that is suitably structured to complement the size and shape of the TSA. Subsequent chemical removal of the TSA template from the supporting molecule reveals a cavity with an intact shape, size and functionality that may then accept a transition state of interest.90, 109 A combined computational and experimental study on a 22residue Zn-finger hydrolase, mimicking the active site of a carbonic anhydrase (CA), has explored two possible mechanisms of hydrolysis by zinc metallozymes via integrating molecular dynamics (MD) simulations, QM/MM geometry optimizations and QM/MM free energy simulations.110 The free energy barrier calculated from the kinetics experiments were in agreement with the computed value for the minimum energy path in the sequential mechanism where the rate limiting step is the formation of the tetrahedral intermediate. More generally, computational studies such as this highlight their utility in validating and understanding the interaction between reaction intermediates and the surrounding species. 3.3 The Hydrophobic Environment As discussed so far, enzymes employ a complicated folded protein structure to afford an internal cavity that compliments

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the chemistry of the active site. In chymotrypsin-like hydrolases, this cavity is composed of hydrophobic amino acid residues. This creates a hydrophobic internal environment that is essential for tuning the electrostatic interactions between the active site functional residues, as well as attracting and binding suitable substrates, stabilizing transition states and facilitating the discharge of reaction products.30, 111 In this respect, it is important to note that both hydrogen bonds and electrostatic effects become stronger, the lower the polarity of the medium. Self-assembled micelles, vesicles, and dendrimers are among the tools available to chemists inspired by this enzyme cavity to recreate the hydrophobic nano-environment.20, 112 Since the late 1950s, the similarities between self-assembled micelles and the folded protein structure of enzymes have provided inspiration for the design of functional surfactant enzyme mimics.113-118 In the particular, the spontaneous selfassembly in solution to yield a hydrophobic environment and functional group interactions are some common features important for the design of enzyme mimics. Nature also employs natural surfactants to assist the function of enzymes in physiological processes, such as the chemistry of bile acid derivatives in animal digestion.113-114

Figure 6. Micellar catalysis. Above the critical micelle concentration (CMC), the self-assembly of amphiphilic surfactant molecules into micelles provides a pseudo phase separation, with an internal hydrophobic environment unique from the bulk solution. Partitioning of reactants into the micellar core can serve to decrease the activation energy of a desired chemical transformation through both kinetic and electrostatic effects, resulting in enhanced reaction rates.117 Surfactants are also known to be intrinsically capable of providing catalytic activity through self-assembly into tertiary structures, such as the formation of micelles.117, 119 Surfactantassisted catalysis is a well-studied phenomenon, whereby selfassembly can create new nano-environments for partitioning reactants, affording reaction conditions that would not normally be encountered in the bulk phase. 120 This can lead to an increased local concentration of reactants in/around the micelle, enhancing the reaction kinetics and leading to increased catalytic performance (Figure 6). In addition, functionalization of the amphiphile head group can be used to impart additional characteristics to the micelle121-123 Seminal work by Bunton and co-workers interpreted the source of catalysis in micellar systems arising from ion binding and electrostatic interactions at the aqueous interface.124

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Numerous studies have looked to recreate the performance of enzymes using functionalized surfactants. Key to this work is the bifunctionality provided by the amphiphilic surfactant structure – a compartmentalized environment provided by the self-assembly of the surfactant into a micelle; and the chemical reactivity tuned by the functionalized head group. An authoritative text by Fendler and Fendler highlights the large volume of work conducted into micellar systems as models of hydrolytic enzymes into the late 1960s.117 Surfactants containing carboxylic acid, oxime, imidazolium, hydroxyl or thiol functionalities (or a combination thereof) were widely explored as hydrolase models during this time period, though reported catalytic rate enhancements were modest at best. Reasons for their poor performance were suggested by Fendler as a lack of rigidity in the dynamic micelle-substrate complex that limits the required functional group interaction, as well as a limited penetration of water. Despite this, an increasing volume of research was conducted into the 1980s into enzyme-inspired, functionalized micellar catalysis, with an excellent review by Ta§cioǧlu consolidating the majority of work conducted during this highly active period. 121 Brown and Bunton reported the first example of a histidinefunctionalized surfactant system that undertakes esterolysis and is resilient to ionization during micelle formation.125-126 This work examined the potential of functional group interaction by forming a co-micelle system with hydroxyl– and imidazolyl– containing surfactants. Moss conducted studies in a similar field, establishing a series of esterolytic surfactant systems based on functionalized amphiphilic head groups containing both functional groups in the same structure.127-129 These relatively simple systems highlighted the increased esterolytic effect of the bifunctional surfactants, giving evidence for a concerted, intramolecular interaction helping to mediate the reaction.129-130 The importance of intramolecular interactions requires particular emphasis here, with work by Page and Jencks simplifying the catalysis borne from these systems as entropically-driven when moving from a bimolecular to a unimolecular reaction.131 Menger also reflects on the importance of intramolecular interactions, suggesting that functional groups brought within Van der Waals contact distances (~3 Å) for finite periods of time may result in enzymelike rate enhancements.16 These results have been supported by the considerable attention of Kunitake, Tonellato and Ihara separately and their coworkers.132-139 They report the design of bifunctional surfactants containing the imidazole ring, hydroxyl group, or both. Numerous approaches to these surfactants are reported and enhanced catalysis is consistently observed for the systems where the catalytic groups are positioned within close proximity on the surfactant polar head group (Figure 7). 1H-NMR has been used to establish a two-step catalytic mechanism, involving an initial nucleophilic attack, and subsequent ratedetermining deacylation step analogous to the serine proteases.129-130, 140 Interestingly, the imidazole unit has been implicated in the catalytic mechanism of many of these studies, with histidine–functionalized systems displaying significant hydrolytic catalysis.141-143

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ACS Catalysis micelles as a suitable nanoparticulate scaffold for the controlled release of drugs, light-harvesting, and bio-inspired catalysis.146 Chun and co-workers have used similar shell-crosslinked micellar systems to perform hydrolytic kinetic resolution of epoxides, again presenting the wide array of possibilities available to the micellar scaffold.147

Figure 7. Hydrolase-inspired multi-functional surfactants. A selection of surfactants investigated as biomimetic hydrolytic catalysts, containing one or more of the catalytic triad functional groups (hydroxyl, acid and imidazole) at their headgroup. (A) The bi-functional (OH-Im) surfactant reported by Kunitake exhibited enhanced catalysis in a co-micellar system with cetyltrimethylammonium bromide (CTAB).138 (B) The cationic bi-functional surfactant explored by Moss gave evidence for a concerted intermolecular interaction between functional groups.129 (C) A multi-functional cationic surfactant with tunable absolute stereo-configuration disclosed by Brown, displaying stereo-selective catalysis 126 (D) Two of the bifunctional surfactants reported by Tonellato, exploring different functional group combinations for maximizing catalysis.132 (E) A selection of the functionalized surfactants described by Ihara, illustrating evidence for an acylation-deacylation catalytic mechanism similar to that of native hydrolases.137 More recently, Dejugnat et al. examined a series of lipopeptides for their organocatalytic properties towards ester hydrolysis and the role of their self-assembled structures in catalysis.144 Synthesis of the catalysts was achieved by grafting fatty acid chains on tripeptides, affording amphiphilic character and selfassembling properties. Insertion of a histidine in the peptide sequence was chosen to bring about organocatalytic activity. Variation of the structures (including peptide sequence and hydrophobic character) led to the formation of various aggregates, from globular objects to fibers. All derivatives containing histidine presented catalytic activity for the hydrolysis reaction of p-nitrophenyl acetate in aqueous solution. The influence of the self-organization on the catalysis was evidenced by the observation of different behaviors between monomers and aggregates. Further work in the field of biomimetic micellar scaffolds has been performed in the past decade by Zhao et al. Hu and Zhao recently reported cross-linked micelles that contained enzymelike active sites for the hydrolysis of activated esters.145 Using molecular imprinting techniques within their micelle, they developed an artificial esterase that displayed both nucleophilic and basic catalysis in an acidic bulk solution as well as control over catalyst selectivity. This built on earlier work by Zhao, who reported the general development of surface-cross-linked

In the work of Chun and co-workers, a thorough computational characterization of the association of amphiphilic triblock copolymers based upon poly(2-oxaline)s with a series of epoxides and diols was performed. This same group also performed potential of mean force (PMF) analysis of steered MD simulations and DFT-based calculations to augment their system characterization, and found their computational results, particularly free energy changes, were in qualitative agreement with experimental observations.147 This group has also performed dissipative particle dynamics simulations to predict the multicompartmental structure of their micelles.148 In contrast to the work described previously, that of Chun and coworkers does not involve the use of an acid-base-nucleophilemediated hydrolysis, instead employing a catalytic metallic center. However, it illustrates the concept of using computational methods, particularly classical MD and QM methods in concert, as a multiscale and versatile tool to assist in the rational design of enzyme mimics employing micellar scaffolds. Vesicle-type architectures – including natural vesicles, generated liposomes, and synthetic polymersomes – are also frequently observed in the field of enzyme mimicry. These differ structurally from micelles in that they contain an enclosed hydrophilic environment compared with the hydrophobic interior of micelles, which is significant in drug delivery, the development of model protocell systems, and particularly for encapsulation of catalytic activity.69, 149 While some examples of functionalized vesicles performing catalysis exist, these mostly employ metallic centers to achieve their catalysis.150-151 An interesting application of vesicles containing catalytic sites, or nanoreactors, lies in the development of functional cellular mimics as a study in the emergence of complex life.152-153 For example, the work of Adamala and Szostak (vida supra) identified mechanisms for the heritable variation of evolutionary fitness by observing competition between model protocells that contained an encapsulated Ser-His dipeptide catalyst (Figure 8).67, 69 Their protocell takes the form of a replicating vesicle containing the Ser-His dipeptide, whereby vesicle growth is preferred over vesicles lacking the simple dipeptide catalyst. While their study did not investigate a heritable catalytic mechanism, the result was sufficient to suggest a relationship between the ability of protocells to catalyze the generation of useful metabolites and the initiation of Darwinian evolution mechanisms. More recently, Maiti and co-workers have investigated the role of dissipative selfassembly in vesicular nanoreactors.149 Traditionally, synthetic self-assembly processes are driven by a gain in free energy, while natural dissipative self-assembly is a process that requires continuous consumption of some molecular fuel source. The ability to thus regulate the formation of vesicular nanoreactors, and thus their catalytic activity, via controlling the fuel source is an attractive prospect that warrants further investigation.149 A further biomimetic vesicular system has been reported by Liu et al., demonstrating a method for constructing eukaryotic cell mimics by loading pH-sensitive synthetic vesicles

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(polymersomes) as organelle mimics inside a biomimetic and functionalized cell membrane.154 The encapsulation of catalyst within synthetic vesicles allowed spatiotemporal control of multiple enzymatic cascade reactions, a significant advance in synthetic biology.

Figure 8. Szostak’s “protocell” catalyst. While non-specific and relatively inefficient, the simple dipeptide Ser-His catalyzes the reaction between LeuNH2 and AcPheOEt generating the product dipeptide AcPheLeuNH2. In the presence of fatty acid vesicles, the dipeptide product is localized into the membrane bilayer, providing a competitive advantage for vesicle growth over vesicles without the Ser-His catalyst.69 3.4 Integration of Active Site, Binding Pocket and Hydrophobic Environment 3.4.1 Macrocycle Based Hydrolytic Enzyme Mimics Bender, Breslow and Tabushi (and co-workers) each expanded separately on the idea of macrocyclic protease mimics with work focused on the internal cavity of cyclodextrins.96, 103, 155 These water-soluble, ring shaped oligomers are frequently composed of 6 or more α-D-glucopyranoside units and present a useful hydrophobic pocket to bind a substrate for catalysis. The chemistry of cyclodextrins can also be tuned further through the inclusion of catalytic groups (such as imidazole and hydroxyl groups) to the macrocycle rim.156-160 This offers the dual benefit of creating an internal environment conducive to a substrate, where it can then also be acted on by a functional moiety near the macrocycle rim in much the same way as native enzymes. Utilizing a simpler approach, Rebek and co-workers made a significant contribution to synthetic enzyme mimics by targeting hydrogen-bonded catalyst conformations.161-163 Fine control of the host cavity is afforded by these systems, which can subsequently align individual substrate species close to the catalytic moieties – a significant advance in synthetic catalyst design. Jiang et al. reported a series of aza-crown ethers functionalized with carboxylic acid side arms as mimicry of the aspartate proteases.164 Significant rate enhancements were observed for these systems when consideration was given to spacing of the acidic functional groups to optimize interaction with a proposed anhydride intermediate. The suggested intra-molecular interaction between functional groups responsible for enhanced catalytic effect in these systems has been well highlighted by Kirby.165-166 This work shows that converting inter– to intra–molecular hydrogen bonding between acid/base pairs, via the formation of 5–8 membered rings, greatly enhances the effectiveness of the catalytic groups. These results support the widely accepted theory of catalysis via “spatio-temporal” effects, whereby functional groups disposed close enough to exclude intervening solvent tend to result in the greatest rate enhancements.16, 73, 167 This effect can also be observed within the core of macrocyclic catalysts such as cyclodextrins, whereby the inclusion of guest molecules drives the displacement of enthalpy-rich water

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molecules from the macrocycle cavity, which can contribute to catalysis.168 However, it has again been questioned whether the acyl-transfer mechanism of the functionalized cyclodextrin systems can be considered true enzyme-mimicking catalysis,169 due to these systems requiring a stoichiometric concentration of catalyst in order to establish an equilibrium complexation with the substrate, prior to subsequent catalytic steps.

Another macrocyclic platform for undertaking hydrolaseinspired catalysis is cucurbiturils. Cucurbiturils are rigid macrocyles composed of glycoluril monomers connected by methylene bridges and provide a hydrophobic cavity for binding of guest molecules similar to cyclodextrins. Several excellent reviews have been published exploring hydrolytic catalysis by cucurbiturils,170-171 with their performance again being attributed to spatio-temporal effects of substrate molecules hosted with the macrocycle cavity. In addition, a propensity for cucurbiturils to preferentially bind cationic substrates has been identified, leading to their exploration as biomimetic, self-sorting systems for molecular recognition.172 Inclusion of guest molecules into the internal cavity of cucurbiturils has been associated with remarkable shifts in pKa of the guest molecules, leading to acceleration of acid-catalyzed hydrolysis reactions.173

Figure 9. Cram’s chymotrypsin mimic. A small molecule mimic of chymotrypsin, including a synthetic catalytic triad with a hydroxyl nucleophile and suitably shaped binding pocket. The model substrate here (the guest) is an alkylammonium ion selected for enhanced complexation with the mimic. Control structures that selectively exclude specific functional groups support the concerted action of the individual structural features (the triad groups and the rigid complexing site) to afford catalysis.174 Limited work has been undertaken to date with regard to designing host molecules that contain the catalytic triad within a single trifunctional molecule. Representative work by Cram and his team successfully synthesized an example of a serine protease mimic (Figure 9).174-175 The molecule effectively combines many of the important structural features of

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chymotrypsin, such as a suitably aligned catalytic triad and a synthetic binding pocket matched to the substrate of choice. Excellent rate enhancements were observed for a model esterolysis reaction, that could even approach enzyme-like catalysis (1011–fold background rate). However, the system requires a 30-step synthesis to produce and is designed specifically for a single substrate, greatly limiting the relevance of this approach outside of the laboratory.

Warshel et al. replicated the host guest catalysis of orthoformate hydrolysis with significant rate acceleration through a series of combinations of computational assessments consisting of free energy perturbation–umbrella sampling (FEP/US) approach and empirical valence bond (EVB). The catalytic effect was concluded to be wholly due to the change in electrostatic contributions to the activated free energy, supporting the claim that the heart of enzyme catalysis is electrostatic transition state stabilisation.179

More recent work by Rebek and co-workers targeted functionalized cavitands as enzyme-inspired catalysts.176 This work effectively combined a well-defined binding pocket provided by a rigid cavitand, with a suitably-positioned catalytic group to deliver a unique environment for undertaking aminolytic catalysis (Figure 10).177 By leveraging the rigid, “vase-like” structure of the cavitand to undertake molecularrecognition, the reactive center of an alkylammonium substrate could be directed toward a catalytic pyridone moiety positioned on the cavitand rim. The dual role of the cavitand in binding and attacking a specifically shaped substrate represents a significant advance in enzyme-inspired catalyst design.

3.4.2 Multi-functional Mimicry of the “Oxyanion Hole” Transition state (TS) analogues attempt to mimic the size, shape and charge density of the enzyme-binding pocket, however a key functional element that supports the active site chemistry in hydrolytic enzymes is the formation of enzyme-TS hydrogen bonds.26, 180 The spatially close and suitably aligned amide groups of specific serine and glycine residues serve these roles in the serine proteases, forming the oxyanion hole.30 The oxyanion hole serves two key roles in the serine proteases: withdrawing electron density from the electrophilic carbonyl of the substrate, making it more susceptible to attack by the serine hydroxyl of the enzyme’s active site; and withdrawing electron density from the charged tetrahedral TS, reducing the activation energy of the acyl-enzyme complex. Outside of the oxyanion hole, hydrogen bonding is responsible for the concerted action of the catalytic triad to tune the pKa of the serine hydroxyl nucleophile, as well as for substrate recognition and forming the complex tertiary structure of the enzyme. Researchers now have a good understanding of the importance of hydrogen bonding for hydrolytic catalysis via activating electrophiles for nucleophilic attack. In particular, the enantioselectivity and asymmetric bond formation afforded by H-bond catalyzed systems is an important feature exploited by both natural enzymes and increasingly by synthetic chemists.181

Figure 10. Rebek’s Cavitand Catalyst. The host structure (catalyst 1) is capable of effectively surrounding a cationic substrate species, positioning it for interaction with an inwardly directed functional group (a single pyridine). The powerful combination of substrate binding and recognition to afford positioning near a catalytic functionality results in significant rate enhancements for a model aminolysis reaction. Recently, Costa et al. utilized a 2-aminobenzimidazole-based ‘deep’ cavitand as a catalyst for the hydrolysis of choline carbonate through a metal-free, enzyme-like mechanism.178 The rate-determining step proceeds through a programmed hydrolysis of carbamoylcholine-cavitand intermediate that may be driven by water molecules surrounding the benzimidazole walls of the cavity.

Ema et al. reported enzyme-like rate accelerations for a transesterification reaction using a compound synthesized to contain a hydroxyl group as a nucleophile and a pyridine group as a base, with an oxyanion hole provided by a (thio)urea group (Figure 11).182 They compare the activity of their system to catalyze the transesterification reaction of vinyl trifluoroacetate with several short-chain alcohols against the background reaction without catalyst. The impressive rate enhancement of 3.8 x 106 above the background reaction (kcat/kuncat) may be due in part to the arrangement of the functional groups that allows the binding of the substrate and stabilization of the transition states in the one conformation. An important finding of this study, supported by earlier work by Wayman and Sammakia, is that the relative acidity of the nucleophilic hydroxyl proton in the catalyst has a significant effect on the overall catalytic effect.183 Tuning the reactivity of the hydroxyl component was achieved by the addition of various nearby electronwithdrawing groups (urea, tri- and penta-fluoro groups), rather than via remote electrostatic interactions as performed by the natural hydrolytic enzymes.

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foldamers and dendrimers, which can afford functional cavities suitable for catalysis.187-190 An extension of this approach is the development of single chain nanoparticles (SCNP), whereby single polymer chains can be selectively collapsed following an external cue to form internal environments reminiscent of native enzymes. The application of metal-containing SCNPs as versatile enzyme mimics has been eloquently highlighted in a recent perspective by Barner-Kowollik et al.191 More generally, the development and explosive interest in controlled “living” polymerizations has provided a diverse palette of techniques to control molecular weight distribution and monomer sequence in polymers and oligomers.192-194 Figure 11. A hydrolase-inspired catalyst containing an oxyanion hole. This serine protease mimic exhibited excellent rate enhancement in the transesterification reaction of an activated vinyl acetate.182 Kheirabadi and co-workers expanded on the hydroxyl-pyridineurea system more recently, utilizing a similar tri-functional catalytic motif attached to spiroligomers for transesterification rate enhancements in a similar range to the Ema study.184 The benefit from the approach developed in this work comes from the stereochemically defined spiroligomer ‘ladder’ backbone that can be tuned to rigidly position the three functional groups suitably for catalysis. Further work has been conducted with functionalized spiroligomers as backbones to align catalytic residues, including additional studies by Houk and Schafmeister as robust mimics of enzymes.185 These systems have been designed using an inside-out computational approach, and while laborious to prepare synthetically, this catalyst platform holds significant merit as a design strategy for a robust serine protease mimic. The Baker group utilized QM methods to construct Cys-His dyads, with suitably positioned hydrogen-bond donors or oxyanion holes, in catalytically inert protein scaffolds for three different target substrates.186 All 214 scaffolds were incorporated with hydrogen bond donors to stabilize the oxyanion intermediate in three sets of designs: 1) by a backbone NH group, 2) by explicit water molecules and 3) with side-chain functional groups. Key highlights of this work include the understanding of the interaction between the backbone NH groups with the carbonyl oxygen being similar to that during the oxyanion formation in hydrolases. The work also highlighted the importance of a catalytic cysteine residue, as well as support from a nearby histidine residue in governing the effectiveness of the catalyst and the geometry of the active site, respectively. 3.4.3 Polymeric and Dendritic Based Hydrolytic Enzyme Mimics Nature has truly remarkable control of molecular sequencing and weight distributions to facilitate the complex structure and chemistry of biological systems. It is the specific amino acid sequence of biopolymers that defines the structure and function of all proteins. Enzymes in particular benefit from the highly specific folding of the protein afforded by the backbone peptide sequence to perform catalysis. A significant challenge for researchers is to approach this level of macromolecular control in a synthetic polymeric system.57 Progress has been made exploring well-defined, synthetic polymer chains such as

Molecularly imprinted polymers (MIPs) have been one of the most widely explored examples of scaffolds for TSAs due to the ease with which subsequent chemical modifications can be made, and the control over the polymer structural rigidity.89, 107, 109, 195-196 The first reported MIP to target mimicry of chymotrypsin was described by Leonhardt and Mosback.197-198 Their system employed Co2+ ions and a protected amino acid template to align imidazole functional groups for subsequent hydrolysis of a structurally similar p-nitrophenyl ester. The metal coordination provides access to a defined cavity structure and ease of template removal; however, template selection and rigidity of the polymer support is vital. Modest rate enhancements were observed for this system (5–7 fold above background), which was then incrementally improved by Ohkubo et al. by employing a phosphonate template as a TSA for p-nitrophenyl acetate.199-200 This early work may have displayed limited rate enhancements due to a lack of selectivity in functional group orientation after removal of the template. In addition, the template selection may have been too closely aligned to the substrate rather than the TS, which has been identified as critical for delivering catalysis.57 Following work by Ohkubo, phosphonate TSAs have received significant attention. In particular, phosphonic ester TSAs were developed as chymotrypsin mimics (Figure 12).199, 201 The tetrahedral phosphorous center provides a good structural mimic for the transition state of chymotrypsin-like hydrolysis reactions and is easily removed from the polymer support by washing with methanol. In addition, the multiple ester bonds provide versatility in the choice of side chains, affording access to a wider range of potential guest substrates. MIPs using phosphonate templates have been developed using copolymerization and pendant grafting to polymers, providing excellent control over the internal environment of the final cross-linked product.202-203 Again, modest esterolytic rate enhancements are observed for many of the phosphonatetemplated materials (5–10 fold above background). However, more challenging amidolysis reactions and substrates such as cholesterol derivatives have been successfully catalyzed using this technology.204-206

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Figure 12. Molecularly imprinted polymers (MIPs) based on hydrolytic enzyme mimics. (a) The similarity between the tetrahedral phosphorous center and the transition state of an esterolysis reaction was harnessed to suitably align the catalytic triad group. (b)–(d) Phosphonate-based transition state analogues with varied functionalization arrangements. Versatility in the side groups of the tetrahedral phosphonic structure affords access to a wide array of transition state size and shapes.199 Devaky et al. also reported an enzyme-inspired polymer catalyst with an imidazole moiety fabricated on multi-walled carbon nanotubes (MWCNT) via molecular imprinting technology.207 The MIPs were formed from the functional monomer methacryloyl-l-histidine, with phenyl 1benzyloxycarbonylamino-4-methoxybenzyl phosphonate as the TSA. The catalytic activities of the TSA-imprinted and nonimprinted polymers towards the hydrolysis of p-nitrophenyl esters were investigated. The TSA-imprinted polymeric MWCNTs revealed substrate specific catalytic activity with dependence on solvent, concentration and pH of the medium. Furthermore, esterolytic reactions by the MWCNT both with and without polymer incorporation were examined, highlighting the effectiveness of the imprinted nanotubes for undertaking catalysis. The issue with MIPs as versatile enzyme mimics lies in the selection of a TSA to develop a suitable binding pocket. This approach inherently rules out substrate versatility in the final MIP material by targeting a unique size and shape of TSA, potentially limiting the application of this technique outside of the laboratory, or where the transition state structure is not previously known. In addition, the characteristic covalent interaction between the enzyme and transition state that occurs during serine protease catalysis has been suggested to be more complicated than can be accounted for using a simple small molecule TSA.54, 208 The increasingly widespread use of computer modelling and combinatorial chemistry may help to offset these issues by allowing a larger library of potential TSA and template structures to be screened, and work in this direction is ongoing.209-213

Figure 13. Merrifield resin supported hydrolytic enzyme mimics. Tuning the local hydrophobicity of the resin particles with an approach analogous to the native enzyme hydrophobic pocket increased the catalytic efficiency. Reprinted with permission from reference 214. Copyright 2017, Elsevier. A much simpler alternative to MIPs is to link an enzymemimicking “active site” randomly to a polymer support. In this way, any catalytic power lost due to non-optimal substrate recognition, may be offset by higher catalyst loadings and significant cost savings. As proof of concept, Connal et al. recently developed a simple one-step synthesis for preparing a supported catalytic system in which the three reactive groups of the catalytic triad (alcohol, imidazole, and carboxylate) are incorporated into a single functional unit. These artificial active sites were coupled to a solid-phase support (Merrifield resin) by a copper(I)-catalyzed azide-alkyne cycloaddition “click” reaction, and their effectiveness as esterolysis catalysts was significantly enhanced (Figure 13).214 Furthermore, tuning the local hydrophobicity of the resin particles with an approach analogous to the native enzyme hydrophobic pocket increased the catalytic efficiency. QM and MD computational modelling were used to probe the catalytic effect and suggested a concerted two-step mechanism and hydrophobic nanoenvironment similar to that of many hydrolases. A specific polymeric material with particular promise for the design of enzyme-inspired macromolecules are those composed of dendrimers. Dendrimers are a type of highly symmetrical macromolecule comprised of repetitively branched monomer units extending outward in layers (generations) from a core.215216 The layered architecture of dendrimers enables encapsulation and isolation of an internal functionality, in much the same way as natural enzymes. The dendron character and the placement of functional groups have been used to tune the nano-environment inside the dendrimer, complementing the activity of the catalytic sites.21, 217-219 Furthermore, functionalization with catalytic groups can also be achieved at the dendrimer surface. This approach is typified by high catalyst loadings and solvent-exposed catalyst moieties which are readily available for interaction with solubilized reactants. This effect is particularly observed in large dendrimers, which tend to adopt a globular conformation with most terminal catalytic groups exposed at the surface.217 The facile control of catalyst

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loading, placement and reactive environment in dendrimers, as well as their displaying characteristics of both heterogenous and homogenous catalysis, has seen their widespread examination as enzyme-inspired catalysts. Breslow reported an early example of dendrimers as mimicry of the macromolecular structure of enzymes, employing a single pyridoxamine functional unit at the dendrimer core and delivering a significant catalytic effect for a selected transaminase model reaction.220 Reymond et al. investigated the contribution of the dendritic structure in catalysis of ester hydrolysis with a systematic peptide dendrimer series of increasing generation number (G1−G4) containing the known catalytic dipeptide sequence Ser-His in all branches (Figure 14).221-224 A strong positive dendritic effect was observed with up to a 100-fold increase in histidine reactivity between G1 and G4. Kinetic studies and isothermal calorimetric titration experiments showed that the strong positive dendritic effect resulted from cooperativity between binding and catalysis.223

Figure 14. A dendrimer-based hydrolytic enzyme mimic. A strong positive dendritic effect was observed with up to 100fold increased histidine reactivity when increasing the number of monomer layers (generations (G)) between G1 and G4. Reprinted with permission from ref 223. Copyright 2004, American Chemical Society. Significant work has been undertaken in relation to placement and number of the catalytic sites, the presence of a metalorganic catalytic core, and substrate selectivity of functionalized dendrimers.217 Selection of an appropriate number of dendron generations and the placement of the catalytic groups have added to the complexity of developing dendrimer-based enzyme mimics.225 Recent study into dendrimers functionalized with non-catalytic amino acids have highlighted that these units also have a role in determining the substrate specificity of the dendrimer.226 In work by Reymond et al., two combinatorial 4-generation peptide dendrimer libraries were prepared, both with and without N-terminal acetylation, thoroughly covering the sequence space using 14 amino acids. Off-bead assays were performed with fluorogenic substrates for aldolase and esterase activities and compared with a model hydrophobic substrate and a standard polyanionic substrate. Different catalytic behavior towards the hydrophobic and trianionic substrates was demonstrated, especially when compared with linear peptides. The dendrimers from the N-acetylation library, with multiple catalytic histidine residues and hydrophobic amino acids, were more active towards the hydrophobic substrate, whereas those from the library without N-acetylation, with mostly cationic residues and no hydrophobic groups, were more reactive towards the trianionic substrate. These findings highlight the similarity between native enzymes and dendritic enzyme-

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mimics for employing remote functional groups to indirectly tune substrate specificity. 3.4.4 Engineered Peptide and Protein Based Hydrolytic Enzyme Mimics The development of enzyme-inspired catalysts tests our understanding of the sequence-to-structure/function relationships in proteins.227 Natural proteins and peptides are versatile molecules for catalyst design, thanks largely to the development of techniques such as gene manipulation, functional selection, and de novo enzyme design. These unique natural structures have become sources of inspiration and innovation, particularly in the design of catalytic antibodies.228229 Peptide-based nanofibers that are built from self-assembly of peptides are thought to be ideal supramolecular frameworks for constructing artificial enzymes because the building blocks of peptides are amino acid residues, and the driving forces for selfassembly are noncovalent interactions, which share many characteristics with natural proteins.230-232 Furthermore, nanofibers built through noncovalent interactions can form amphiphilic architectures, in which the functional groups are in close proximity and establish additional noncovalent interactions that could contribute to the catalytic activity. Qi et al. developed an artificial hydrolytic enzyme by combining the catalytic Ser-His-Asp triad with Nfluorenylmethoxycarbonyl diphenylalanine (Fmoc-FF), followed by co-assembly of the peptides into nanofibers (CoAHSD) (Figure 15).233 The self-assembly of the nanofibers provides a means for bringing multiple functional groups into proximity, analogous to the folded tertiary structure of enzymes. Comparing the self-assembled catalytic nanofibers (SA-H) with different amino acid configurations reveals increased catalytic activity of the SA-H materials containing serine, histidine, and aspartate residues (at a 40:1:1 ratio) as opposed to the SA-H materials containing only histidine residues. The authors attributed the well-ordered nanofiber structure and the synergistic effects of serine and aspartate residues as contributing to the enhancement in activity. Additionally, they used molecular imprinting to further enhance the activity of the peptide-based artificial enzyme by templating the substrate p-nitrophenyl acetate. In this way, the catalytic Ser-His-Asp triad residues could be suitably aligned for interaction with the desired substrate, drawing similarities with the binding pocket of the hydrolases. They observed the activity of the imprinted co-assembled nanofibers to be 7.86-fold greater than that of the non-imprinted fibers, and 13.48-fold that of the non-assembled architectures.

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Figure 15. Peptide fiber-based hydrolytic enzyme mimics. The well-ordered nanofiber structure and the synergistic effects of serine and aspartate residues contribute to the enhancement in hydrolytic activity. Reprinted with permission from ref 233. Copyright 2016, American Chemical Society. Zhang et al. employed a similar approach utilizing selfassembled peptide nanofibers containing residues of the catalytic triad.234 In this study, self-assembled short peptides containing a range of catalytic residues were examined for their esterolytic effect. Interestingly, when the short peptides were embedded in a matrix of peptide nanofibers, they exhibited a much higher catalytic efficiency than the peptide nanofibers without incorporation of the short catalytic peptides. The authors suggest that the well-ordered nanostructure is an attractive scaffold for developing new artificial hydrolytic enzymes. Furthermore, the cytotoxicity of the peptide nanofibers was examined against human cells, indicating excellent biocompatibility. Woolfson et al. inserted functional catalytic triads into a hyperstable heptameric α-helical barrel protein.235 Twenty-one mutations were introduced to form seven Cys-His-Glu catalytic triads, with the resulting protein hydrolyzing p-nitrophenyl acetate with activities matching the most-efficient redesigned hydrolytic enzymes based on natural protein scaffolds. In total, seven such triads have been engineered into a heptameric αhelical barrel, which resulted in hydrolytic activities comparable to those achieved in previous enzyme redesigns using natural scaffolds without metal cofactors. Moreover, the peptide-based architecture that was described allows the predictable and facile introduction of standard and noncanonical amino acids, providing further control over the catalytic mechanism of the de novo assemblies. The authors highlight the possibilities for using highly stable, mutable and bottom-up architectures as scaffolds for the precise introduction of catalytic function. Wang, Qi and co-workers have taken this concept a step further by installing a photo-responsive azobenzene unit into a peptide chain containing a catalytic histidine that can assemble into nanofibres.236 On exposure to light, the change in stereo configuration of the azobenzene group serves to disassemble the nanofibers, resulting in a concomitant reduction in hydrolytic activity (Figure 16). The authors suggest that proximity effects as well as the hydrophobic nanoenvironment present within the peptide nanofiber assists catalysis. The ability to position catalytic groups within suitable binding pockets to achieve selective catalysis has also been illustrated recently by Gorin and coworkers.237 In this study, an imidazole catalytic moiety is immobilized into a DNA aptamer as the substrate recognition domain, resulting in highly selective hydrolysis of the chosen model substrate, while remaining unreactive to alternative substrates.

Figure 16. Photo-responsive Catalysis. The self-assembly of a short peptide functionalized with catalytic histidine and a photo-responsive azobenzene unit can be tuned by exposure to light. The catalytic activity is modulated by the (dis)assembly of the peptide nanofiber through proximity effects and an internal hydrophobic environment. Reprinted with permission from ref 236. Copyright 2018, Royal Society of Chemistry. In artificial enzyme design, identifying the structure of the active site is critical. However, achieving this via crystal structures ignores the conformational flexibility of peptides in solution due to their existing in different physio-chemical phases.238-239 Thus, the use of computational methods to sample the conformational space of enzymes is of increasing interest. In a study of cyclic peptide-based hydrolytic enzyme mimics, Stavrakoudis et al. studied the catalytic activity of the best model candidate out of 192 peptide candidates as serine protease mimics by applying a fast conformational search and MD calculations.240 They defined the optimal conditions for directing the three amino acid residues Ser-His-Asp by their D/L replacements and checking the ‘symmetry’ of a series of branched cyclic peptides to act as a catalyst. A modest 4.6-fold improvement in the catalytic rate was achieved, reinforcing the fact that computer simulations can assist the process of designing catalytic peptide-based enzyme models. Combinatorial chemistry has also been harnessed in the identification of suitable hydrolytic enzyme mimics. For example, Albada et al. studied triazacyclophane-scaffolded peptides and generated a library of 19683 tripodal synthetic receptor molecules incorporating three different peptide arms (temporarily N-terminal protected) that perform hydrolysis of 7-acetoxycoumarin as substrate.241 Three sets of amino acids containing traditionally basic (His, Lys), nucleophilic (Ser, Cys) or acidic (Asp, Glu) residues, as well as additional nonfunctional hydrophobic amino acid residues, were incorporated into the peptide design to give different combinations of catalytic triads. Although many of the peptide arm designs included combinations of the catalytic triad, only a relatively small number exhibited catalytic activity under the conditions investigated. Sequence analysis of the active receptors indicated that His (catalytic) or Lys (non-catalytic) residues served to mediate substrate hydrolysis, reinforcing the prerequisite of suitable residue alignment in order to maximize catalysis. Schmuck et al. identified small peptides as efficient metal-free phosphorester hydrolases from a combinatorial library of 625 octapeptides.242 The library consisted of engineered octapeptides with a defined sequence element incorporated at specific fixed positions and different combinations of amino acids at other variable positions to induce a folded conformation in solution. In contrast to the work by Albada et al., it was

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observed that the rate enhancement of peptide hydrolysis is influenced mostly by the number of histidine moieties, but also upon the peptide sequence, as the latter assists in substrate binding and orientation.243 These studies support the hypothesis that minor changes in the peptide sequence result in a drastic effect on the catalytic activity, with a well-defined direction for future combinatorial approaches suggested through analyzing different amino acid arrangements. A notable recent study highlights the close relationship between protein folding and function, demonstrating the design of a stereochemically-bent 16-residue -hairpin polypeptide as a successful hydrolase enzyme mimic, acting on a p-nitrophenyl acetate substrate.244

3.4.5 Nanoparticulate Hydrolytic Enzyme Mimics Nanoparticles (NPs) have attracted increasing attention in the construction of hydrolase mimics due to their unique physiochemical properties, such as the comparable size to native hydrolases, high surface area to volume ratio, the presence of a large number of catalytically active sites on their surface and the availability of multifunctional reactive groups for modification and further functionalisation.58, 245-249 Furthermore, the multifunctional reactive groups can be used to anchor NPs on a support, while remaining fully dispersible yet conformationally constrained, thus enabling them to act cooperatively in catalytic processes. The comparable dimensions of NPs and natural hydrolytic enzymes offer an excellent opportunity to deploy nanoparticulate hydrolytic enzyme mimics where natural hydrolytic enzymes are typically used. The use of nanomaterials as enzyme mimics is a burgeoning field of research, with some recent reviews describing the general progress toward effective “nanozyme” enzyme mimics.250-252 A few recent hydrolase-inspired designs will be illustrated here. Pasquato and co-workers observed that N-methylimidazolecoated gold NPs essentially behave like a hydrolytic enzyme in the hydrolysis of 2,4-dinitrophenyl acetate.249 Later, the same group investigated gold NPs coated with a mixed monolayer, in which the terminal carboxylate of phenyl alanine and the imidazole of histidine were presented on the surface of the gold NPs.253 This chemical functionality, as well as a microenvironment on the gold NP surface that is different from the bulk solution, draws many similarities to that of the catalytic site of hydrolases.254 It was reported that the surfaced-confined functional groups operate in a cooperative manner in the hydrolysis process. The carboxylate and protonated imidazole groups act as a general base and acid respectively, resulting in a 300-fold enhancement in the catalytic efficiency of the hydrolytic process at low pH values.253-254 A similarly functionalized NP (proximal imidazole and carboxylate units) composed of graphene oxide on a polymer bead was shown recently by Zhang to be an effective hydrolaseinspired catalyst. By complexing Zn2+ ions into the NP architecture, the authors report an increased hydrolytic effect when degrading an organophosphorus substrate, with potential application in chemical weapon remediation.255

Figure 17. Peptide fiber based hydrolytic enzyme mimics. The well-ordered nanofiber structure and the synergistic effects of histidine and aspartate residues contribute to the enhancement in hydrolytic catalysis activity on the surface of monolayer protected gold clusters (Au MPC). Reprinted with permission from ref 256. Copyright 2012, American Chemical Society. Scrimin and Prins et al. reported catalytically active peptide– Au nanoparticle complexes, obtained by assembling small peptide sequences on the surface of cationic self-assembled monolayers on gold NPs (monolayer-protected gold clusters (Au MPC)) (Figure 17).256 When bound to the surface, the peptides accelerate the transesterification of the p-nitrophenyl ester of N-carboxybenzylphenylalanine by more than 2 orders of magnitude. The gold nanoparticle serves as a multivalent scaffold for bringing the catalyst and substrate into close proximity, but also creates a local microenvironment that further enhances the catalysis. The supramolecular nature of the ensemble permits the catalytic activity of the system to be modulated in situ. This effect was further highlighted by Koksch, whereby hydrolytic activity of a peptidefunctionalized Au MPC could be regulated by rationally adjusting peptide conformation from a random coil to a coiledcoiled structure on immobilization to the NP surface.257 It was proposed that this conformational change resulted in enhanced interactions between remote glutamate and histidine residues, leading to peptide topologies more suited for undertaking hydrolysis. As an alternative to the cationic self-assembled monolayer, Liu et al. used -cyclodextrin-modified gold NPs and obtained a 2654-fold enhanced reaction rate compared to the uncatalyzed hydrolysis of dinitrodiphenyl carbonate, with an interesting parallel to systems employing cyclodextrins in isolation.155, 258 Kuchma et al. investigated the reactivity of cerium oxide nanoparticles (CNPs) and the resultant hydrolysis with phosphate ester bonds.259 It was reported that CNPs cleave the phosphate ester bonds in pNPP, ATP and o-phospho-Ltyrosine, but not DNA as the phosphate groups are too sterically hindered to take part in nucleophilic substitution. 4. SUMMARY AND OUTLOOK The synthesis of a true mimic of a hydrolytic enzyme is a complex, difficult and worthy target. Mimicking one key aspect of enzyme structures in isolation, such as the active site, transition state binding, or the hydrophobic pocket has been frequently realised, and a variety of these systems have shown some level of hydrolytic activity. However, the overall catalytic efficiency of these simple model systems has seldomly approached that of native enzymes. Considering the broad

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applications of hydrolytic enzymes in industry, such as food production, laundry detergents and biomass conversion, the development of unique and adjustable biomimetic scaffolds will allow hydrolytic enzyme mimics the potential to substitute their natural counterparts. This will be particularly relevant for a wide variety of applications with inherently unfavorable environmental stressors such as temperature extremes, salt concentration, and harsh pH conditions. From the representative examples reviewed here, it is apparent that significant advances have been made in the development of hydrolytic enzyme mimics, however critical challenges remain before we can realize enzyme-inspired systems that challenge native proteins. Rational design and assembly of individual factors is one way to optimize these systems, and necessitates an interdisciplinary approach involving computational modelling, creative synthesis, and catalyst screening. Hydrolytic enzyme crystal structures are available, however correctly identifying representative in vivo structures, and understanding the transition states and intermediates of reactions that are associated with such enzymes is still required to provide a complete picture of the reaction mechanism. In particular, computational modelling is a useful tool for creating novel enzyme mimics and explaining observed phenomena, but currently lacks predictive strength. An additional challenge lies in the widespread focus of past studies on activated substrates such as the nitrophenyl esters. Few works have applied unactivated substrates due to their difficulty in hydrolysis and the convenience that the nitrophenyl group affords in terms of kinetic analysis. Undertaking reactions that are comparative to native enzymes, such as the hydrolysis of unactivated esters, amides and proteins with hydrolytic enzyme mimics under mild conditions remains a challenging target for ongoing research. Furthermore, selfassembled molecules, nanoparticles, polymers, metal organic frameworks, and newly established porous materials are promising scaffolds for the installation of hydrolytic enzyme mimics. The specific recognition and binding of amide and ester groups, combined with the nanoscale environment provided by these materials will undoubtedly facilitate enhanced hydrolytic catalysis. In short, there is still a long way to go before we are able to construct “true” hydrolytic enzyme mimics, incorporating multiple, selective structural features. Mimicry of hydrolytic enzymes is by no means a mature area of research largely because of the difficulties outlined in this review, and because research efforts in this area need to be expanded. Success in this area will have far-reaching impact in both industrial applications, and in enhancing our understanding of biological systems.

Funding from the US Army International Technology Center Pacific (ITC-PAC FA5209-14-C-0017 to L.A.C.), the Defense Science Institute (L.A.C.), a Veski Innovation Fellowship (L.A.C.), a John Stocker Postgraduate Scholarship (M.D.N and L.A.C), an Endeavour Research Fellowship (M.D.N), an Australian Nanotechnology Travelling Fellowship (M.D.N) and an Australian Research Council Georgina Sweet Laureate Fellowship (M.L.C).

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AUTHOR INFORMATION Corresponding Author

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* E-mail: [email protected]

Author Contributions ‡These authors contributed equally. The manuscript was written through contributions of all authors.

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ACKNOWLEDGMENTS

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