Structural Determinants of Yeast Protein-Protein Interaction Interface Evolution at the Residue Level

Interfaces of contact between proteins play important roles in determining the proper structure and function of protein-protein interactions (PPIs). Therefore, to fully understand PPIs, we need to better understand the evolutionary design principles of PPI interfaces. Previous studies have uncovered that interfacial sites are more evolutionarily conserved than other surface protein sites. Yet, little is known about the nature and relative importance of evolutionary constraints in PPI interfaces. Here, we explore constraints imposed by the structure of the microenvironment surrounding interfacial residues on residue evolutionary rate using a large dataset of over 700 structural models of baker's yeast PPIs. We find that interfacial residues are, on average, systematically more conserved than all other residues with a similar degree of total burial as measured by relative solvent accessibility (RSA). Besides, we find that RSA of the residue when the PPI is formed is a better predictor of interfacial residue evolutionary rate than RSA in the monomer state. Furthermore, we investigate four structure-based measures of residue interfacial involvement, including change in RSA upon binding (ΔRSA), number of residue-residue contacts across the interface, and distance from the center or the periphery of the interface. Integrated modeling for evolutionary rate prediction in interfaces shows that ΔRSA plays a dominant role among the four measures of interfacial involvement, with minor, but independent contributions from other measures. These results yield insight into the evolutionary design of interfaces, improving our understanding of the role that structure plays in the molecular evolution of PPIs at the residue level.