Thus the following analysis is based on the cycle-closure DDG values. Table summarizes the MUE and RMSD compared to experiment. The overall MUE obtained with GPU-TI of AMBER using the AMBER FF14SB/GAFF1.8 force field (AMBER for short) is 1.17 kcal/mol (0.27 kcal/mol larger than FEP+. Similarly, the RMSD is a bit higher for AMBER: 1.50 kcal/mol versus 1.14 kcal/mol for FEP+. Moreover, in our current work, we did not apply replica exchange, which could help enhance the overall sampling and facilitate equilibrium between different λ simulations. Future work will explore the role sampling (both in λ-space and phase space) plays on these systems versus the effect of force field errors. We also converted the DDG to DG's for each ligand and plotted them against experimental values in Figure . We can see AMBER fared a little worse than FEP+. Out of the 199 ligands, 5 ligands (2.5%) for Schrödinger and 18 ligands (9.0%) for AMBER are more than 2kcal/mol off from experiment. Mutations involving large van der Waals radii changes, like Br to H or I to H, tend to have larger errors. We further analyzed the mutations based on the "size" of the mutation; whether there is ring appearance/disappearance or whether there is ring type change (for example, pyridine to benzene). We classified mutations that involve 3 heavy atoms changing or more as "big change" mutations, and the others as "small change" mutations. AMBER performs well for "big change" as well as "small change" mutations : 151 of the 194 "big change" mutations (~80%) have errors less than 2 kcal/mol, 99 of which have errors less than 1 kcal/mol; 107 of the 136 "small change" mutations have errors less than 2 kcal/mol, 99 of which have errors less than 1 kcal/mol. Compared to "big change" mutations, a larger percentage of "small change" mutations have errors less than 1 kcal/mol: 69% for "small change" vs 51% for "big change" mutations. What's more, ring disappearance/appearance and ring type change are also often seen in mutation studies and they're present in this data set also. From our analysis, we find AMBER performs well for both: 54 of 68 ring disappearance/appearance mutations have errors less than 2 kcal/mol, 35 of which have an error less than 1 kcal/mol; 52 of 78 ring type change mutations have errors less than 2 kcal/mol, 29 of which have an error less than 1 kcal/mol.