Distinguishing foldable proteins from nonfolders: When and how do they differ?

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. Proteins 2002;49:15–23. © 2002 Wiley‐Liss, Inc.