(51b) Proteins Repurposed: Augmenting Biomaterial and Biocatalyst Function with Noncanonical Amino Acids

The genetic code has been deciphered, and researchers are now developing genetic methods to outfit proteins, Nature’s flagship polymers, with an expanded set of noncanonical amino acids (NCAAs). Despite these advances, the unique mapping of a given amino acid sequence to a specific protein function – the “protein code” – remains mysterious. Poor understanding of the protein sequence-to-function relationship limits our ability to rationally design new proteins with predictable characteristics. What if we could use designer NCAAs to bypass this limitation, and decide for ourselves what a given amino acid sequence should do?

In this talk, I will present a new approach to biomaterials and biocatalyst design that uses designer NCAAs to predictably augment and transform protein function. In the realm of biomaterials, I will recount how the incorporation of a noncanonical leucine surrogate into a telechelic protein enabled precise control over polymer dynamics in model protein hydrogels, ultimately leading to the elucidation of a new and ubiquitous polymer transport mechanism in reversible macromolecular networks. In the realm of biocatalysis, I will describe our ongoing intensive efforts to design catalytically active NCAAs that effectively distill the essential reactivity of certain enzymes into single chemofunctional residues. By embedding these residues into heterochiral peptide frameworks, highly selective organocatalysts that catalyze numerous abiological transformations have been obtained. In particular, I will discuss the recent successful deployment of Pi-methyl histidine, a genetically encodable histidine analogue, as a nucleophilic catalyst for sulfamate group transfer. Taken together, these results establish a new paradigm for repurposing proteins with specific, user-defined functions.

References:

Rapp, P.B., Omar, A.K.; Shen, J.J.; Buck, M.E.; Wang, Z.G.; Tirrell, D.A. Analysis and control of chain mobility in protein hydrogels. J. Am. Chem. Soc., 2017, 139 (10), 3796–3804.

Rapp, P.B.; Omar, A.K.; Silverman, B.R.; Wang, Z.G.; Tirrell, D.A. Mechanisms of diffusion in associative polymer networks: evidence for chain hopping. J. Am. Chem. Soc. 2018, 140 (43), 14185–14194.

Rapp, P.B.; Murai, K.; Ichiishi, N.; Leahy, D.K.; Miller, S.J. Catalytic sulfamoylation of alcohols with activated aryl sulfamates. Org. Lett. 2020, 22 (1), 168–174.

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