title: Equilibrium collapse and the kinetic 'foldability' of proteins.
abstract: An important element of protein folding theory has been the identification of equilibrium parameters that might uniquely distinguish rapidly folding polypeptide sequences from those that fold slowly. One such parameter, termed sigma, is a dimensionless, equilibrium measure of the coincidence of chain compaction and folding that is predicted to be an important determinant of relative folding kinetics. To test this prediction and improve our understanding of the putative relationship between nonspecific compaction of the unfolded state and protein folding kinetics, we have used small-angle X-ray scattering and circular dichroism spectroscopy to measure the sigma of five well-characterized proteins. Consistent with theoretical predictions, we find that near-perfect coincidence of the unfolded state contraction and folding (sigma approximately 0) is associated with the rapid kinetics of these naturally occurring proteins. We do not, however, observe any significant correlation between sigma and either the relative folding rates of these proteins or the presence or absence of well-populated kinetic intermediates. Thus, while sigma approximately 0 may be a necessary condition to ensure rapid folding, differences in sigma do not account for the wide range of rates and mechanisms with which naturally occurring proteins fold.
authors.affiliation: Department of Applied Physics, Stanford University, Stanford, California 92343, USA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Millet
authors.forename: Lara E
authors.initials: LE
authors.lastname: Townsley
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
authors.forename: Sebastian
authors.initials: S
authors.lastname: Doniach
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Plaxco
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D002942:Circular Dichroism; D003574:Cytochrome c Group / Q000737:chemistry*; D004529:Egg White; D006736:Horses; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D009113:Muramidase / Q000737:chemistry*; D009132:Muscles / Q000201:enzymology; D004856:Postural Balance; D017510:Protein Folding; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000737:chemistry*; D014961:X-Ray Diffraction; D000097024:Acylphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D003574:Cytochrome c Group; D009113:Muramidase; D025801:Ubiquitin; D000097024:Acylphosphatase