Fig. shows the convergence of the VDD charges and the QM/MM reaction energy as well as the corresponding sensitivities to global point charge variations (cf. Fig. for the same plot PCVA-constructed QM regions deliver overall lower sensitivities regarding VDD ligand charges (see Fig. ), which marks an expected behavior because high-sensitivity residues are included in the QM region by PCVA. The convergence of the charge sensitivities is similar to the analysis for distance-based QM regions (cf. Fig. ) with a fast convergence for Mg 2+ , a constant behavior for CAT, and jumps for SAM with a slightly decreasing trend.