Conformational Entropy and Protein Stability

Abstract

A principal driving force for the folding of a protein to its globular state is the tendency for the hydrophobic side chains of amino acids to cluster to avoid contact with the solvent (Kauzmann 1959). However, by itself hydrophobicity is too strong a driving force to account for the stabilities of proteins. An early estimate (Tanford 1962) suggested the hydrophobic interaction contributed the order of 180 kcal/mol toward condensation in myoglobin, but experiments (Tanford 1962; Pace 1975; Privalov and Kechinashuili 1974; Privalov 1979) show that free energies of folding are only about 1/10th as large. Hence, it is clear that there is at least one additional strong driving force in the opposite direction, toward the unfolded state, but with magnitude almost equal to that of the hydrophobic interaction. Thus, the marginal observed stabilities of globular proteins appear to be due to a small difference of large driving forces. The principal candidate for the opposing force is the conformational entropy: the conformational freedom of the molecule should clearly be greater in the many unfolded configurations than in the folded state. Statistical thermodynamic theory has recently been developed to account for this balance of forces (Dill 1985; Dill et al. 1988). Our purpose here is to focus on the role of the conformational entropy.