Ranked at 2 nd and 3 rd were DDM/FEP/MBAR/ParamChem and DD/GROMOS-53A6_glyc/SPC/MD (Figure ). The PMF/GAFF-RESP/TIP4PEW/SMD ranked 4 th , estimating binding free energies that were too favorable and leading to RMSE and MAE values of 27.26 and 26.38 kcal/mol. Due to the multiple differences between methods employed, it is difficult to compare or determine if and what factor or combination of factors contributed to the differences in model BFE accuracy.