The role of stability in protein evolution

Abstract

Amino acids have been tuned throughout evolution such that their interactions lead the overall protein to predominantly fold into the same structure at physiological conditions. How often a protein finds its native structure at equilibrium is measured by its change in the Gibbs free energy of the folding process (ΔG). This thesis explores biophysical constraints on and evolutionary consequences of proteins’ optimal ΔG values. We explore whether stability is likely to influence long-term evolution through mutations that cause a loss of function or gain in toxicity (Chapter 1). In Chapter 2, we fully develop the framework to understand the proteomic relationship between abundance and evolutionary rate. We assess the differences between ΔG and another stability proxy called melting temperature to determine whether conclusions reached with available experimental melting temperature data are transferable (Chapter 3). Finally, in Chapter 4 we mathematically motivate an important assumption tying ΔG to evolution: the average change in ΔG from a single mutation. Through bioinformatically-tested mathematical modeling, we elucidate the role protein stability plays in explaining the universal protein abundance – sequence evolutionary rate correlation and the Gaussian form of single mutant ΔG effects seen across proteins.