MOLECULAR-BASIS OF COOPERATIVITY IN PROTEIN-FOLDING .4. CORE - A GENERAL COOPERATIVE FOLDING MODEL

The cooperative nature of the protein folding process is independent o f the characteristic fold and the specific secondary structure attribu tes of a globular protein. A general folding/unfolding model should, t herefore, be based upon structural features that transcend the peculia rities of alpha-helices, beta-sheets, and other structural motifs foun d in proteins. The studies presented in this paper suggest that a sing le structural characteristic common to all globular proteins is essent ial for cooperative folding. The formation of a partly folded state fr om the native state results in the exposure to solvent of two distinct regions: (1) the portions of the protein that are unfolded; and (2) t he ''complementary surfaces,'' located in the regions of the protein t hat remain folded. The cooperative character of the folding/unfolding transition is determined largely by the energetics of exposing complem entary surface regions to the solvent. By definition, complementary re gions are present only in partly folded states; they are absent from t he native and unfolded states. An unfavorable free energy lowers the p robability of partly folded states and increases the cooperativity of the transition. In this paper we present a mathematical formulation of this behavior and develop a general cooperative folding/unfolding mod el, termed the ''complementary region'' (CORE) model. This model succe ssfully reproduces the main properties of folding/unfolding transition s without limiting the number of partly folded states accessible to th e protein, thereby permitting a systematic examination of the structur al and solvent conditions under which intermediates become populated. It is shown that the CORE model predicts two-state folding/unfolding b ehavior, even though the two-state character is not assumed in the mod el. (C) 1993 Wiley-Liss, Inc.