The solvophobic theory for the prediction of molecular conformations and biopolymer bindings in solutions with recent direct experimental tests

Molecules exposing considerable microsurface areas to the surrounding solvent such as amino acids, nucleotide bases in biopolymers, or various drug molecules, antigens, and substrates, tend to be pulled apart or pushed together as the case may be by the surrounding solvent medium. These solvophobic forces and their quantitative theory were introduced sometime earlier [O. Sinanoglu, in Molecular Associations in Biology, B. Pullman, Ed. (Academic, New York, 1968), pp. 427–445; and references therein]. The forces involve both enthalpy and entropy effects. The case in water had been shown to involve particularly strong forces but not differing in kind from other solvents. There are still somewhat contradictory views on the aqueous case, referred to in the literature as “hydrophobic bonding” treated as a phenomena unique to water and previously thought to involve only entropic effects. The temperature dependence and volumetric effects on the earlier type of “hydrophobic bonding” are presently not always reconcilable with recent experimental evidence. By contrast, the solvophobic force theory allows the calculation of the full solvent effect on various association or isomerization equilibria using its quite rigorous relations and basic data derived with it from liquids and solutions. [cf., e.g., for an early application to cis-trans azobenzene isomerization, T. Halcǐoǧlu and O. Sinanoglu, Ann. N.Y. Acad. Sci., 158, 308 (1969)]. The solvophobic force theory had also introduced as a measurable new quantity, “the thermodynamic microsurface area change of a reaction,” which is now finding considerable use in protein chemistry [cf., e.g., F.M. Richards and T. Richmond, in CIBA Symposium Proceedings on Molecular Interaction and Activity in Proteins (CIBA, New York, 1977)]. Solvophobic force theory has been tested and applied recently in detail in high pressure liquid chromatography (HPLC) by C. Horvath, W. Melander, and I. Molnar [J. Chromatograph. 125, 123 (1976)] who verified the predicted temperature, molecular surface area, and salt concentration dependence. It worked well when applied in detail to the complicated methanol–water mixtures as well. The theory also gave the first a priori derivation of the experimentally well-known protein salting-in–salting-out curve [W. Melander and C. Horvath, Arch. Biochem. Biophys. 183, 200 (1977)]. We have now extended the theory further with new basic derivations which eliminate the need for the direct calculation of some cumbersome effects. The theory has also been recently applied to a number of new areas including drug-receptor interactions, aqueous amino acid interactions, and to multicomponent phase equilibria; the latter also of chemical engineering interest. Solvophobic interactions, although part statistical thermodynamical in nature, were shown to be usable as if they were an ordinary U(R) potential added on to quantum-chemical intrinsic in vacuo potentials for prediction of conformations in solution [O. Sinanoglu, in The World of Quantum Chemistry, R. Daudel and B. Pullman, Eds. (Reidel, Dordrecht, 1974)]. There have also been some recent applications that illustrate the convenience of our solvophobic theory in correcting for solvent effects once quantum-mechanical molecular electronic structures and potential-energy surfaces are computed.