The relationship between interfacial overlap and functional divergence in the yeast protein-protein interaction...

Protein-protein interactions (PPIs) and genetic interactions are central to cellular function. We investigate their relationship in the structurally resolved yeast PPI network, specifically the relationship between PPI structural divergence and functional divergence. For pairs of proteins ("interactor pairs") binding to the same target protein, we measure PPI structural divergence using interfacial overlap (the number of interfacial residues in the target protein shared between the interactor pair), and functional divergence using genetic interaction profile similarity. We find a significant and robust negative correlation between interfacial overlap and genetic interaction profile similarity, where interactor pairs with large shared interface on the target protein tend to perform divergent phenotypic-level functions. This relationship is the strongest when functional similarity is measured by genetic interaction profile similarity, rather than by gene ontology-based functional similarity. Our findings suggest that competitive binding drives functional divergence of proteins at the phenotypic level.