SOLVATION FREE-ENERGIES ESTIMATED FROM MACROSCOPIC CONTINUUM THEORY - AN ACCURACY ASSESSMENT

The solvation thermodynamics of a set of small organic molecules is studied using a simple continuum model. Transfer from vapor or cyclohexane to water is decomposed into three steps: first the atomic partial charges of the solute are removed, then it is transferred into aqueous solution, and then its partial charges are restored. The electrostatic steps are treated using continuum electrostatics; the hydrophobic transfer step is treated using atomic ''solvation parameters'' or ''surface tensions''. Vapor-to-water transfer free energies of 35 neutral compounds were estimated, including analogues of 17 amino acid side chains. Variants of the model were tested, using from one to three atom types, each with its own surface tension. With a single surface tension, taken from literature data on linear alkanes, the data were reproduced with a root-mean-square (rms) error of 1.3 kcal/mol. Using up to three atom types did not improve the fit significantly. A model with up to eight atom types, but no electrostatic term, behaved no better. The model was also applied to cyclohexane-to-water transfer of the 17 amino acid side chain analogues considered above. Using a single, adjustable, atomic surface tension, the data were fit with an rms error of 1.2 kcal/mol, giving a microscopic surface tension of 19 +/- 6 cal/(mol Angstrom(2)), in agreement with experimental estimates for n-alkanes. Models with up to three atom types did not behave significantly better. Thus parametrized, the model was used to calculate the potential of mean force between two N-methylacetamide molecules in solvents of dielectric constant 80, mimicking water, and 2.2, mimicking carbon tetrachloride.