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  1. Polypeptides, as the synthetic analogues of natural proteins, are an important class of biopolymers that are widely studied and used in various biomedical applications. However, the preparation of polypeptide materials from the polymerization of N-carboxyanhydride (NCA) is limited by various side reactions and stringent polymerization conditions. Recently, we report the cooperative covalent polymerization (CCP) of NCA in solvents with low polarity and weak hydrogen-bonding ability (e.g., dichloromethane or chloroform). The polymerization exhibits characteristic two-stage kinetics, which is significantly accelerated compared with conventional polymerization under identical conditions. In this Account, we review our recent studies on the CCP, with the focus on the acceleration mechanism, the kinetic modeling, and the use of fast kinetics for the efficient preparation of polypeptide materials. By studying CCP with several initiating systems, we found that the polymerization rate was dependent on the secondary structure as well as the macromolecular architecture of the propagating polypeptides. The molecular interactions between the α-helical, propagating polypeptide and the monomer played an important role in the acceleration, which catalyzed the ring-opening reaction of NCA in an enzyme-mimetic, Michaelis–Menten manner. Additionally, the proximity between initiating sites further accelerated the polymerization, presumably due to the cooperative interactions of macrodipoles between neighboring helices and/or enhanced binding of monomers. A two-stage kinetic model with a reversible monomer adsorption process in the second stage was developed to describe the CCP kinetics, which highlighted the importance of cooperativity, critical chain length, binding constant, [M]0, and [M]0/[I]0. The kinetic model successfully predicted the polymerization behavior of the CCP and the molecular-weight distribution of resulting polypeptides. The remarkable rate acceleration of the CCP offers a promising strategy for the efficient synthesis of polypeptide materials, since the fast kinetics outpaces various side reactions during the polymerization process. Chain termination and chain transfer were thus minimized, which facilitated the synthesis of high-molecular-weight polypeptide materials and multiblock copolypeptides. In addition, the accelerated polymerization enabled the synthesis of polypeptides in the presence of an aqueous phase, which was otherwise challenging due to the water-induced degradation of monomers. Taking advantage of the incorporation of the aqueous phase, we reported the preparation of well-defined polypeptides from nonpurified NCAs. We believe the studies of CCP not only improve our understanding of biological catalysis, but also benefit the downstream studies in the polypeptide field by providing versatile polypeptide materials. 
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    Free, publicly-accessible full text available July 28, 2024
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  3. Abstract

    The recent advances in accelerated polymerization ofN-carboxyanhydrides (NCAs) enriched the toolbox to prepare well-defined polypeptide materials. Herein we report the use of crown ether (CE) to catalyze the polymerization of NCA initiated by conventional primary amine initiators in solvents with low polarity and low hydrogen-bonding ability. The cyclic structure of the CE played a crucial role in the catalysis, with 18-crown-6 enabling the fastest polymerization kinetics. The fast polymerization kinetics outpaced common side reactions, enabling the preparation of well-defined polypeptides using an α-helical macroinitiator. Experimental results as well as the simulation methods suggested that CE changed the binding geometry between NCA and propagating amino chain-end, which promoted the molecular interactions and lowered the activation energy for ring-opening reactions of NCAs. This work not only provides an efficient strategy to prepare well-defined polypeptides with functionalized C-termini, but also guides the design of catalysts for NCA polymerization.

     
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  4. Abstract

    Enzymes provide optimal three-dimensional structures for substrate binding and the subsequent accelerated reaction. Such folding-dependent catalytic behaviors, however, are seldom mechanistically explored with reduced structural complexity. Here, we demonstrate that the α-helix, a much simpler structural motif of enzyme, can facilitate its own growth through the self-catalyzed polymerization ofN-carboxyanhydride (NCA) in dichloromethane. The reversible binding between the N terminus of α-helical polypeptides and NCAs promotes rate acceleration of the subsequent ring-opening reaction. A two-stage, Michaelis–Menten-type kinetic model is proposed by considering the binding and reaction between the propagating helical chains and the monomers, and is successfully utilized to predict the molecular weights and molecular-weight distributions of the resulting polymers. This work elucidates the mechanism of helix-induced, enzyme-mimetic catalysis, emphasizes the importance of solvent choice in the discovery of new reaction type, and provides a route for rapid production of well-defined synthetic polypeptides by taking advantage of self-accelerated ring-opening polymerizations.

     
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  5. Synthetic polypeptides derived from the ring-opening polymerization of N -carboxyanhydrides can spontaneously fold into stable secondary structures under specific environmental conditions. These secondary structures and their dynamic transitions play an important role in regulating the properties of polypeptides in self-assembly, catalysis, polymerization, and biomedical applications. Here, we review the current strategies to modulate the secondary structures, and highlight the conformation-specific dynamic properties of synthetic polypeptides and the corresponding materials. A number of mechanistic studies elucidating the role of secondary structures are discussed, aiming to provide insights into the new designs and applications of synthetic polypeptides. We aim for this article to bring to people's attention synthetic polymers with ordered conformations, which may exhibit association behaviors and material properties that are otherwise not found in polymers without stable secondary structures. 
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  6. Ribozymes synthesize proteins in a highly regulated local environment to minimize side reactions caused by various competing species. In contrast, it is challenging to prepare synthetic polypeptides from the polymerization of N -carboxyanhydrides (NCAs) in the presence of water and impurities, which induce monomer degradations and chain terminations, respectively. Inspired by natural protein synthesis, we herein report the preparation of well-defined polypeptides in the presence of competing species, by using a water/dichloromethane biphasic system with macroinitiators anchored at the interface. The impurities are extracted into the aqueous phase in situ, and the localized macroinitiators allow for NCA polymerization at a rate which outpaces water-induced side reactions. Our polymerization strategy streamlines the process from amino acids toward high molecular weight polypeptides with low dispersity by circumventing the tedious NCA purification and the demands for air-free conditions, enabling low-cost, large-scale production of polypeptides that has potential to change the paradigm of polypeptide-based biomaterials. 
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  7. Abstract

    Inspired by protein polymerizations, much progress has been made in making “polymer‐like” supramolecular structures from small synthetic subunits through non‐covalent bonds. A few regulation mechanisms have also been explored in synthetic platforms to create supramolecular polymers and materials with dynamic properties. Herein, a type of reactive regulator that facilitates the dimerization of the monomer precursors through dynamic bonds to trigger the supramolecular assembly from small molecules in an aqueous solution is described. The supramolecular structures are crystalline in nature and the reaction coupled assembly strategy can be extended to a supramolecular assembly of aromatic amide derivatives formed in‐situ. The method may be instructive for the development of supramolecular nanocrystalline materials with desired physical properties.

     
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