Structural energetics of protein stability and folding cooperativity

Numerous studies have demonstrated that the folding/unfolding transitions of globular proteins involve very few or no thermodynamically stable intermediate structures between the folded and unfolded states. Recently we have developed a hierarchical partition function formalism aimed at gaining an understanding of the cooperative nature of thermal transitions in proteins. The energetic terms in the partition function are correlated to structural properties of the protein, namely buried surface areas and number of residues. Using phosphoglycerate kinase and myoglobin as examples, it is shown that intermediately folded states are destabilized by two features: the unfavorable exposure of apolar surface area on regions of the intermediate structure remaining folded, and a decreased gain in configurational entropy for portions of the polypeptide chain which are adjacent to those regions remaining folded.