An Assessment of Quaternary Structure Functionality in Homomer Protein Complexes.

It has been recently suggested that a significant fraction of homomer protein-protein interfaces evolve neutrally, without contributing to function, due to a hydrophobic bias in missense mutations. However, the fraction of such gratuitous complexes is currently unknown. Here, we quantified the fraction of homodimers where multimerization is unlikely to contribute to their biochemical function. We show that: 1) ligand binding-site structure predicts whether a homomer is functional or not; the vast majority of homodimers with multichain binding-sites (MBS) are likely to be functional, while in homodimers with single-chain binding-sites (SBS) and small to medium interfaces, quaternary structure is unlikely to be functional in a significant fraction-35%, even up to 42%-of complexes; 2) the hydrophobicity of interfaces changes little with the strength of selection, and the amino acid composition of interfaces is shaped by the "hydrophobic ratchet" in both types, but they are not in a strict equilibrium with mutations; particularly cysteines are much more abundant in mutations than in interfaces or surfaces; 3) in MBS homomers, the interfaces are conserved, while in a high fraction of SBS homomers, the interface is not more conserved than the solvent-accessible surface; and 4) MBS homomer interfaces coevolve more strongly with ligand binding sites than the interfaces of SBS homomers, and MBS complexes have higher capacity to transfer information from ligands across the interfaces than SBS homomers, explaining the enrichment of allostery in the former.