The water-octanol partition coefficient is an important physicochemical property for small molecule drug design. Here, we report our participation in the SAMPL6 logP 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 logP 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 logP units) but good on the remaining eight (deviations all less than 1 logP 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.

中文翻译：

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用Drude极化力场预测SAMPL6挑战中类药物分子的分配系数。

水-辛醇分配系数是小分子药物设计的重要理化性质。在这里，我们报告了我们通过使用Drude极化力场在水相和1-辛醇相中利用自由能扰动（FEP）计算参与了SAMPL6 logP预测挑战。我们预测的均方根误差（RMSE）和平均绝对误差（MAE）等于1.85和1.25 logP单位。错误分布不均。在11种SAMPL6溶质中，FEP / Drude对三个分子（偏差均大于2 logP单位）表现非常差，但对其余8个分子（均小于1 logP单位的偏差）表现良好。我们发现，虽然FEP在水中能在一纳秒内很好地收敛，但是在1-辛醇中进行模拟需要更长的模拟时间，并且可能需要更独立的运行来进行采样。我们还发现1-辛醇尽管是一种非极性溶剂，但仍能使溶质分子极化并与它们形成稳定的氢键。最后，我们尝试通过QM / Drude计算来重新加权FEP轨迹，并在仿真设置中讨论可能的警告。