Expanding the functions and properties of protein-based polymers via unnatural amino acid incorporation

Inspired by nature, scientists have harnessed the natural protein translation machinery to produce intricate and precise protein-based polymers (PBPs) – composed of natural amino acid monomers and assembled on the nano-to-macro scale – for drug and gene delivery, to sense the environment, to produce valuable molecules, and to grow cells and tissues. Beyond the chemical repertoire of natural amino acids, incorporation of unnatural building blocks in PBPs can further expand polymer function by endowing new physical and biophysical properties. Here, I will present the synthesis and applications of PBPs, such as Elastin- and Resilin-like Polypeptides, that contain programmable combinations of natural and unnatural amino acids (uAAs). Evolution of efficient translation machinery for the multi-site incorporation of various uAAs enable the recombinant synthesis of PBPs with novel functions such as for tunable half-life extension of peptides and small molecules, the de-novo design of light-responsive PBPs, and the elucidation of sequence-function relationship in temperature-responsive PBPs. This work provides the basis for a new approach to template directed synthesis of PBPs containing diverse synthetic chemical groups, with the goal of advancing our ability to rationally design polymers with new or improved functions.