found that in COMT, the activation barrier shows a much smaller sensitivity with respect to the choice of the QM region than the reaction energy. Therefore, we will not consider activation barriers and focus on the reaction energies in the present work. In addition to the VDD charges obtained with the undistorted MM charges for the different QM regions considered above, Fig. includes the VDD charges obtained with collective point-charge variations ∆q tot MM with ∆q between +0.005 and -0.005. The corresponding sensitivities (defined in analogy to Eq. ( ) for the VDD charges and evaluated numerically using a symmetric two-point finite difference formula [Eq. ( )] with ∆q = 0.005) are plotted in Fig. .