Free energy perturbation study of octanol/water partition coefficients: Comparison with continuum GB/SA calculations

Molecular dynamics (MD) free energy perturbation (FEP) simulations were car ried 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. Rel ative free energies of solvation were computed for each solute in both solv ents, and these results were used to estimate the relative octanol/water pa rtition coefficients (log P-ow). The relative octanol/ water partition coef ficients were in good agreement with experimental log P-ow values (average unsigned error = 0.74 log units), if one omits the acetamide-acetone simula tion 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 compu tationally much more efficient GB/SA calculations proved to be more accurat e (average unsigned error in log P-ow = 0.50 log units) than FEP for this s et of 12 solutes.