Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology

It has been suggested that the evolution of protein complexes is significantly influenced by stochastic, non-adaptive processes. Using ligand binding as a proxy of function, we show that the structure of ligand-binding sites significantly influences the evolution of protein complexes. We show that homomers with multi-chain binding sites (MBSs) evolve new functions slower than monomers or other homomers, and those binding cofactors and metals have more conserved quaternary structure than other homomers. Moreover, the ligands and ligand-binding pockets of homologous MBS homomers are more similar than monomers and other homomers. Our results suggest strong evolutionary selection for quaternary structure in cofactor-binding MBS homomers, whereas neutral processes are more important in complexes with single-chain binding sites. They also have pharmacological implications, suggesting that complexes with single-chain binding sites are better targets for selective drugs, whereas MBS homomers are good candidates for broad-spectrum antibiotic and multitarget drug design. [Display omitted] •Ligand binding site structure significantly influences protein function evolution•MBS homomers have more similar ligand binding pockets than monomers and other homomers•Cofactor and metal-binding MBS homomers have more conserved QS than other homomers•MBS homomers are promising targets for developing antibiotics and multitarget drugs Homomers with ligand binding sites involving multiple protein chains (MBS homomers) evolve new functions slower than other homomers and monomers, and the ones binding cofactors/metals also have more conserved quaternary structure (QS). These complexes are likely to be promising targets for antibiotics and multitarget drugs.