Free Energy Perturbation Study of Octanol/Water Partition Coefficients:  Comparison with Continuum GB/SA Calculations

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.