(604c) Rational Design of Random Heteropolymers As Structured Proteins

Biopolymers exhibit an unparalleled degree of sequence precision, enabling them to achieve a myriad of functional properties in natural systems. Inspired by the intimate sequence-structure-function correlation in proteins, polymer scientists have long strived to design new functional materials by controlling the monomer sequence in synthetic polymers. However, even with a limited set of monomers, the sequence space for synthetic polymers is massive. Therefore, new approaches are needed to navigate through this vast sequence space and accelerate the pace of material discovery. Leveraging advances in de novo protein design and computational sequence analysis, random heteropolymers (RHPs) containing three and more comonomers have been explored to achieve protein-like properties. Orthogonal to the approaches pursuing monomeric sequence specificity, RHP samples a reduced sequence space within a defined monomer composition. By tuning the segmental-level chemical characteristics, RHPs have demonstrated a variety of functions, such as stabilizing proteins in foreign environments and facilitating transmembrane transport.

Here, we investigated the feasibility of designing RHPs to mimic the functions of structured proteins such as enzymes. We first determined twenty-eight pairwise reactivity ratios for five methacrylate monomers directly from multi-monomer RAFT copolymerization experiments. This allows us to account for the influences of competitive monomer addition and the reversible activation/deactivation equilibria on the copolymerization kinetics. Understanding the interdependent reaction kinetics in five-monomer copolymerization lays a foundation for leveraging in silico design to link segmental chemical heterogeneity with the intrinsic comonomer reactivities in synthesis. Subsequently, we tailored the segmental chemical heterogeneity in a family of RHPs constructed from these five methacrylate monomers. Analysis of the catalysis kinetics indicates that, compared to natural enzymes, these RHPs exhibit 10-fold greater peroxidase activities towards hydrophobic substrate. The inherent conformational flexibility of RHPs, coupled with the segmental chemical heterogeneity achieved through statistical sequence control, empowers these polymers to demonstrate catalytic capabilities in various reactions, robustness at interfaces, and efficient degradation of environmentally persistent chemicals. Beyond exploring new avenues for replicating protein functions using synthetic polymers, present work provides a framework to design functional polymers by considering the segmental sequence distribution.