We see that the molecular mechanics-based predictions exhibit a rightward fanning out of the error distributions, i.e. errors become larger as molecular weight increases. Moreover, we stress that not only does the distribution become wider to the right, the proportion of errors within the -2 to 2 region between the dashed black lines becomes smaller and smaller as one moves to the right of the x axis. This means that not only do errors become larger with For the TIP3P + GAFF2.11 combination, we performed energy minimization, heating, density equilibration, preproduction equilibration, and production dynamics in four independent replicas. Overall results for the hydration free energy estimates, computed from the production stages of the four replicas, are nearly indistinguishable -the 4 replicas agree with each other up to an R 2 = 0.99 (SI Fig. ). Finally, we compare the latest version of GAFF -2.11 -to version 1.81 using the TIP3P water model. We find a minor difference in performance -GAFF2.11 produced an R 2 of 0.84 and an RMSE of 1.78 ± 0.05 kcal/mol; GAFF1.81 produced and R 2 of 0.88 and an RMSE of 1.70 ± 0.05 kcal/mol with a slightly narrower error distribution (SI Fig. ).