Molecular dynamics (MD) free energy perturbation (FEP) simulations were carried out in order to obtain insights into the structures and dynamics of a series of small organic solutes in water and water-saturated 1-octanol. Relative free energies of solvation were computed for each solute in both solvents, and these results were used to estimate the relative octanol/water partition coefficients (log P o w). The relative octanol/water partition coefficients were in good agreement with experimental log P o w values (average unsigned error = 0.74 log units), if one omits the acetamide−acetone simulation which proved problematic. Partition coefficients were also calculated using the newly developed GB/SA octanol continuum solvation model in order to compare the MD-FEP and continuum model results. Interestingly, the computationally much more efficient GB/SA calculations proved to be more accurate (average unsigned error in log P o w = 0.50 log units) than FEP for this set of 12 solutes.

A continuum solvation model has been developed for octanol on the basis of the generalized Born/surface area (GB/SA) formalism. This model was parameterized to fit experimental octanol free energies of solvation for a training set of 66 diverse organic solutes. The resulting model is able to reproduce experimental octanol free energies of solution with an unsigned average error of 0.50 kcal/mol when using the recently developed Merck molecular force field (MMFF). Results are poorer when the model is applied to other force fields such as OPLS, where the atomic charges vary significantly from MMFF. The GB/SA octanol model can be used in conjunction with computed or experimental aqueous free energies of solvation to calculate log P ow directly. The average unsigned error in calculated log P ow values for the same set of compounds is 0.37.

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