We now turn to another aspect of this work with important implications for drug design and discovery. While the overall R 2 and RMSE metrics appear favorable, what often gets overlooked in this type of analysis is the dependence of prediction accuracy on ligand molecular weight. Our results demonstrate that for all three water models, gross errors become much more prevalent beyond the 200 molecular weight region. This is clearly problematic in a drug design setting where the HFE is one component of the free energy of binding (ΔGbind); HFE also has value in and of itself as a predictor of ligand solubility.