The plot of the QM/MM reaction energies for the different QM regions in Fig. also includes the reaction energies obtained for collective point-charge variations ∆q tot MM , whereas Fig. shows the corresponding sensitivities δ∆E reaction QM/MM . The point charge variation leads to significant changes in the reaction energy especially for a variation of ∆q = ±0.005, for which changes of up to 8 kcal/mol could be observed for small QM regions. The convergence behavior of the energy itself is not affected by the point charge variation. The sensitivity starts decreasing strongly with region 4 while the reaction energy converges towards the one found for the largest QM region 9. An exception is found for QM region 8, for which the reaction energy does not follow this trend. This can be attributed to the inclusion of four rather critical charged residues in region 8, namely the negatively charged GLU5, GLU63, and ASP168 as well as the positively charged LYS45. Remarkably, for this outlier the sensitivity is also strongly increased.