Overall, these first point charge variation tests show that small changes in the MM point charges have an impact on the QM region. While VDD charges and the reaction energy slowly converge for larger QM regions, the corresponding sensitivities to global point-charge variations decrease, whereas outliers are accompanied by an increased sensitivity. Generally, sensitivities are smaller for reaction energies closer to our best estimate (i.e., the reaction energy obtained for the largest QM region). This indicates that the sensitivity to global point-charge variations might indeed be useful as an indicator for the reliability of QM/MM calculations, and that systematically reducing this sensitivity could be a promising strategy for the systematic construction of the QM region.