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-ow). The relative octanol/ water partition coefficients were in good agreement with experimental log P-ow 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-ow = 0.50 log units) than FEP for this set of 12 solutes.