Abstract
Using detailed hydrogen bonding, surface exposure, internal environment, and solvent interaction calculations on several proteins, in conjunction wit data from quantum mechanical hydrogen-bonding studies, various contributions to the free energy of globular estimated and their likely relative significance discussed. A picture emerges of globular proteins as extremely well-fitting jigsaw-puzzles, in which no single driving force dominates the marginal stability of the native conformation. Rather, the folded structure is seen as the result of a complex global maximization of several strongly-interacting driving forces. In particular, the necessity to maintain very efficient internal hydrogen-bonding, and the role of the solvent as a hydrogen-bond sink, are stressed as strong constraints on the (incomplete) maximization of hydrophobic effects. The possible significance of internal dipole-induced dipole interactions is discussed tentatively. Although quantitative estimates of the various contributions remain uncertain, consideration of effective force constants suggests that polar, including solvent, interactions may largely determine the overall curvatures of the native conformation's potential well, and be important in controlling the flexibility of local regions which are important for the exact positioning of groups during enzyme catalysis, as well as the molecule's overall dynamics. In contrast, hydrophobic interactions change less for small geometrical perturbations, and seem more relevant to directing the folding protein. along a path to a region in configurational space where the polar interactions can switch on for the final "docking".