Molecular Foundations of Accessibility in Genotype-Phenotype Maps

How do the biochemical properties of proteins shape evolution? Addressing this question is central to solving issues facing humanity, from rapidly evolving antibacterial and pesticide resistant organisms to achieving predictive protein engineering. Although advancements in sequencing and screening methodologies have made functional characterization of millions of mutations plausible, a predictive understanding of how proteins evolve is still lacking. Understanding how proteins evolve requires detailed knowledge of the map evolution navigates—the genotype-phenotype map—and where major sources of unpredictability, such as epistasis, come from. The genotype-phenotype map is determined by universal physical and biochemical rules. These rules dictate how macromolecules fold into functional forms, how components in regulatory networks interact, and how organism respond to environmental fluctuations. This defines what is––and is not––accessible to evolution. In this dissertation, we address two factors that shape evolutionary accessibility in proteins: 1) how epistasis can arise from the thermodynamic ensemble of macromolecules and 2) how the distribution of protein function in genotype-phenotype maps facilitates the evolution of new functions