title: Protein folding and binding can emerge as evolutionary spandrels through structural coupling.
abstract: Binding interactions between proteins and other molecules mediate numerous cellular processes, including metabolism, signaling, and gene regulation. These interactions often evolve in response to changes in the protein's chemical or physical environment (such as the addition of an antibiotic). Several recent studies have shown the importance of folding stability in constraining protein evolution. Here we investigate how structural coupling between folding and binding--the fact that most proteins can only bind their targets when folded--gives rise to an evolutionary coupling between the traits of folding stability and binding strength. Using a biophysical and evolutionary model, we show how these protein traits can emerge as evolutionary "spandrels" even if they do not confer an intrinsic fitness advantage. In particular, proteins can evolve strong binding interactions that have no functional role but merely serve to stabilize the protein if its misfolding is deleterious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutational events. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. In contrast, for proteins with both functional binding and deleterious misfolding, evolution may be highly predictable at the level of biophysical traits: adaptive paths are tightly constrained to first gain extra folding stability and then partially lose it as the new binding function is developed. These findings have important consequences for our understanding of how natural and engineered proteins evolve under selective pressure.
authors.affiliation: Department of Physics and Astronomy and.
authors.forename: Michael
authors.initials: M
authors.lastname: Manhart
authors.affiliation: Department of Physics and Astronomy and BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, NJ 08854 morozov@physics.rutgers.edu.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Morozov
mesh_terms: D000220:Adaptation, Biological / Q000502:physiology*; D003198:Computer Simulation; D019143:Evolution, Molecular; D005828:Genetics, Population; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000502:physiology*; D017510:Protein Folding; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins
keywords: evolutionary spandrels; fitness landscapes; folding stability; protein evolution; protein interactions