Predicting partition coefficients of drug-like molecules in the SAMPL6 challenge with Drude polarizable force fields

The water-octanol partition coefficient is an important physicochemical property for small molecule drug design. Here, we report our participation in the SAMPL6 log P prediction challenge with free energy perturbation (FEP) calculations in the water phase and in the 1-octanol phase using Drude polarizable force fields. Root mean square error (RMSE) and mean absolute error (MAE) of our prediction are equal to 1.85 and 1.25 log P units. The errors are not evenly distributed. Out of eleven SAMPL6 solutes, FEP/Drude performed very badly on three molecules (deviations all larger than 2 log P units) but good on the remaining eight (deviations all less than 1 log P unit). We find while FEP converges well within one nanosecond in water, simulations in 1-octanol need much longer simulation time and possibly more independent runs for sampling. We also find out that 1-octanol, albeit being a non-polar solvent, still polarizes solute molecules and forms stable hydrogen bonds with them. At the end, we attempt to reweight FEP trajectories with QM/Drude calculations and discuss possible caveats in our simulation setup.