Running nearly 20 times more computing with TIP3P and GAFF1.7 achieves a modest improvement in accuracy -R 2 = 0.87 (from 100 ns of total sampling per ligand) vs 0.84 from our results (5.25 ns of total sampling); RMSE = 1.53 ± 0.07 kcal/mol (from 100 ns of sampling) vs 1.78 ± 0.05 kcal/mol from our work (5.25 ns of sampling). This suggests that for drug-like molecules, which tend to be larger than the ones examined here, simulations will require at least another order of magnitude or tens to hundreds of nanoseconds of total sampling time with a 3-point water model to reliably converge.