title: The highly cooperative folding of small naturally occurring proteins is likely the result of natural selection.
abstract: To illuminate the evolutionary pressure acting on the folding free energy landscapes of naturally occurring proteins, we have systematically characterized the folding free energy landscape of Top7, a computationally designed protein lacking an evolutionary history. Stopped-flow kinetics, circular dichroism, and NMR experiments reveal that there are at least three distinct phases in the folding of Top7, that a nonnative conformation is stable at equilibrium, and that multiple fragments of Top7 are stable in isolation. These results indicate that the folding of Top7 is significantly less cooperative than the folding of similarly sized naturally occurring proteins, suggesting that the cooperative folding and smooth free energy landscapes observed for small naturally occurring proteins are not general properties of polypeptide chains that fold to unique stable structures but are instead a product of natural selection.
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Watters
authors.forename: Pritilekha
authors.initials: P
authors.lastname: Deka
authors.forename: Colin
authors.initials: C
authors.lastname: Corrent
authors.forename: David
authors.initials: D
authors.lastname: Callender
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varani
authors.forename: Tobin
authors.initials: T
authors.lastname: Sosnick
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D002942:Circular Dichroism; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017354:Point Mutation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012641:Selection, Genetic; D013816:Thermodynamics
chemical_list: D011506:Proteins