Rational design of reduced alphabet proteins

Abstract

Conventional protein design approaches generally utilize a design space limited to the standard 20 amino acid alphabet (AAA), restricting the incorporation of unnatural amino acids, and associated novel functions. Reducing the standard AAA can free up codon space for the abovementioned purpose along with accelerating in silico protein design. However, previously designed reduced AAA protein variants have shown little to no activity relative to their wild-type counterparts. The overarching goal of this thesis was to identify and employ the protein design rules observed in nature for the development of a generalizable RAP design pipeline. Since dynamics are integral to maintaining protein function, data presented in this thesis investigates the structural dynamics of proteins using Molecular Dynamics simulations. This insight into the structural dynamics of proteins assisted in designing RAPs and in the characterization of a receptor targeted by a virus pathogenic to humans, offering potential pharmaceutical and astrobiology applications.