title: Evolution of specificity in protein-protein interactions.
abstract: Hub proteins are proteins that maintain promiscuous molecular recognition. Because they are reported to play essential roles in cellular control, there has been a special interest in the study of their structural and functional properties, yet the mechanisms by which they evolve to maintain functional interactions are poorly understood. By combining biophysical simulations of coarse-grained proteins and analysis of proteins-complex crystallographic structures, we seek to elucidate those mechanisms. We focus on two types of hub proteins: Multi hubs, which interact with their partners through different interfaces, and Singlish hubs, which do so through a single interface. We show that loss of structural stability is required for the evolution of protein-protein-interaction (PPI) networks, and it is more profound in Singlish hub systems. In addition, different ratios of hydrophobic to electrostatic interfacial amino acids are shown to support distinct network topologies (i.e., Singlish and Multi systems), and therefore underlie a fundamental design principle of PPI in a crowded environment. We argue that the physical nature of hydrophobic and electrostatic interactions, in particular, their favoring of either same-type interactions (hydrophobic-hydrophobic), or opposite-type interactions (negatively-positively charged) plays a key role in maintaining the network topology while allowing the protein amino acid sequence to evolve.
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts.
authors.forename: Orit
authors.initials: O
authors.lastname: Peleg
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge Massachusetts.
authors.forename: Jeong-Mo
authors.initials: JM
authors.lastname: Choi
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge Massachusetts. Electronic address: shakhnovich@chemistry.harvard.edu.
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: D000595:Amino Acid Sequence; D030562:Databases, Protein; D019143:Evolution, Molecular; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D011506:Proteins