Somewhat surprisingly, the OPC model produced a lower RMSD and a higher RMSE (R 2 = 0.67, RMSE = 2.54 ± 0.05 kcal/mol), whereas OPC3 performed similarly to TIP3P (R 2 = 0.81, RMSE = 2.18 ± 0.07 kcal/mol). Notably, there is near perfect agreement between the 3-point water models TIP3P and OPC3 (R 2 = 0.97, RMSE = 0.97 ± 0.07, SI Fig. ), far more than between OPC and OPC3 (R 2 = 0.79, RMSE = 2.02 ± 0.06). It is also notable that the majority of points lie above the x = y identity line for all three water models. Consequently, the density distribution curves for the prediction errors or residuals (ΔGexperimental -ΔGcalculated) are left-shifted from the x = 0 kcal/mol line (Fig. ). In the case of a near-perfect prediction, the density distribution curve is tall and narrow, tightly centered around x = 0 kcal/ mol; the poorer the predictions, the lower the peak and the wider the distribution. Among the three water models, TIP3P has the tallest and narrowest error distribution. Again, the distribution for the 3-point OPC3 is very similar in shape, only slightly shorter and wider, whereas the OPC distribution is appreciably different with larger errors (residuals) being much more prevalent than with TIP3P and OPC3 where the majority of predictions fall within 2 kcal/ mol of the experimental values (the region between the dashed black lines in Fig. ).