It should be noted that the NEQ approach by design leads to occasional occurrence of extreme work values in the forward direction when the ligand is coupled in the protein environment. Such extreme values are inevitable in NEQ simulations and compromise accuracy and precision of this approach, which undermines its reliability. We discuss this aspect in detail in the Supporting Information (see Table , Figures S1 and S2 and the related section). The results presented in this study have been obtained after ignoring all work values >1000 kcal/mol.