As starting point, we consider the minimal QM/MM model with QM region 1, i.e., for our COMT test case only the ligands and the catalytically active magnesium ion are included in the QM region. For single-point energy calculations of the geometry-optimized reactant and product structures, we calculate the sensitivity of the QM/MM energy with respect to variations of a single amino acid ∆q aa,i MM,I [cf. Eq. ( )]. Here, we use ∆q = -0.5, i.e., the total charge of the considered amino acid is decreased by 0.5 while an equal charge of opposite sign is distributed over all other MM atoms.