An A_c value of 1 indicates perfect convergence across the 21 λ) of a windows; a value of 0 indicates that the simulations have not even begun to converge. Interestingly, the TIP3P distribution is by far the right-most, followed by OPC3, demonstrating that the 3-point models have achieved the most convergence given a fixed amount of simulation time. It could thus be expected that 3-point water models reach convergence faster and require less simulation time than 4-and especially 5-point models. Moreover, with all three water models examined here, there is a discernible dependence between molecular weight and convergence -the higher the weight, the lower the A_c metric (SI Fig. ), indicating that larger ligands require longer simulations to converge. Further still, there is significant agreement between the convergence estimates among the different water models (SI Fig. ). We should also keep in mind the composition and inherent biases in the FreeSolv set itself, which is mostly composed of small, low molecular weight organic molecules with few or no rotatable bonds (SI Fig. ), which nicely aligns with our circumstances of limited computational resources. Additionally, the majority of FreeSolv ligands have HFEs below 0 and logP < 4. This situation is not typical for drug-like molecules but lends itself to constructing a data set of fragment-like compounds which would be useful in validating free energy techniques on larger ligands, built up from these fragments, as would be encountered in a real drug design scenario.