Abstract
The structure of ligand-binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multichain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologs, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand-binding-site structure shapes allosteric signal transduction pathways, and whether the structural similarity of binding sites influences the evolution of allostery. Our analyses show that: 1) allostery is more frequent among MBS complexes than in SBS complexes, particularly in homomers; 2) in MBS homomers, semirigid communities and critical residues frequently connect interfaces and thus they are characterized by signal transduction pathways that cross protein-protein interfaces, whereas SBS homomers usually not; 3) ligand binding alters community structure differently in MBS and SBS homomers; and 4) except MBS homomers, allosteric proteins are more likely to have homologs with similar binding site than nonallosteric proteins, suggesting that binding site similarity is an important factor driving the evolution of allostery.