title: Distinguishing foldable proteins from nonfolders: when and how do they differ?
abstract: When a denatured polypeptide is put into refolding conditions, it undergoes conformational changes on a variety of times scales. We set out here to distinguish the fast events that promote productive folding from other processes that may be generic to any non-folding polypeptide. We have apply an ab initio folding algorithm to model the folding of various proteins and their compositionally identical, random-sequence analogues. In the earliest stages, proteins and their scrambled-sequence counterparts undergo indistinguishable reductions in the extent to which they explore conformation space. For both polypeptides, an early contraction occurs but does not involve the formation of a distinct intermediate. Following this phase, however, the naturally-occurring sequences are distinguished by an increase in the formation of three-body correlations wherein a hydrophobic group desolvates and protects an intra-molecular hydrogen bond. These correlations are manifested in a mild but measurable reduction of the accessible configuration space beyond that of the random-sequence peptides, and portend the folding to the native structure. Hence, early events reflect a generic response of the denatured ensemble to a change in solvent condition, but the wild-type sequence develops additional correlations as its structure evolves that can reveal the protein's foldability.
authors.affiliation: Department of Biochemistry and Molecular Biology and the Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA. trsosnic@midway.uchicago.edu
authors.forename: Tobin R
authors.initials: TR
authors.lastname: Sosnick
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Berry
authors.forename: Andrés
authors.initials: A
authors.lastname: Colubri
authors.forename: Ariel
authors.initials: A
authors.lastname: Fernández
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins; D019277:Entropy; D007700:Kinetics; D007782:Lactoglobulins / Q000737:chemistry; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012097:Repressor Proteins / Q000737:chemistry; D025801:Ubiquitin / Q000737:chemistry; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D004268:DNA-Binding Proteins; D007782:Lactoglobulins; D011506:Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins