Prediction of properties from simulations: Free energies of solvation in hexadecane, octanol, and water

Monte Carlo (MC) statistical mechanics simulations have been carried out fo r more than 200 organic solutes, including 125 drugs and related heterocycl es, in aqueous solution. The calculations were highly automated and used th e OPLS-AA force field augmented with CM1P partial charges. Configurationall y averaged results were obtained for a variety of physically significant qu antities including the solute-water Coulomb and Lennard-Jones interaction e nergies, solvent-accessible surface area (SASA), and numbers of donor and a cceptor hydrogen bonds. Correlations were then obtained between these descr iptors and gas to liquid free energies of solvation in hexadecane, octanol, and water and octanol/water partition coefficients. Linear regressions wit h three or four descriptors yielded fits with correlation coefficients, r(2 ), of 0.9 in all cases. The regression equation for log P(octanol/water) on ly needs four descriptors to provide an rms error of 0.55 for 200 diverse c ompounds, which is competitive with the best fragment methods. For water, t he expanded data set of 85 solutes and improved statistical analyses bring into question the significance of the Lennard-Jones and surface area terms that have been featured in prior linear-response treatments. The results ar e sensitive to the choice of partial charges for the solute atoms; poor rep resentation of some functional groups can lead to the need for specific cor rections in the regression equations. This is expected to also be true for force-field-based scoring functions for protein-ligand binding. In all case s, the present descriptors that emerge as most significant sensibly reveal the key physical factors that control solvation, especially solute size in organic solvents and electrostatic interactions in water. Furthermore, addi tional MC simulations for solutes in both water and ethanol clearly demonst rate that the key differential between water and alcohols is the greater hy drogren-bond-donating ability of water, which explains the significance of a solute's hydrogen-bond-accepting; ability for log P(octanol/water).