For the avidin complex, given the smaller size of the ligand compared to the FKBP12 complex, we evaluated the accuracy of the predicted protein-ligand interaction energy by comparing it with actual QM/MM calculations. Single point QM/MM calculations were performed on frames taken from a 2 ns long ML/MM production run, and the electrostatic coupling energy (i.e. the electrostatic protein-ligand interaction), was compared to that obtained at the ML/MM level. For comparison, the interaction at the MM level was computed for the same structures. The non-electrostatic component of the interaction was omitted in the analysis since its values are equal for all methods.