Regarding the VDD charges (Fig. ), there are only very small differences between the different PCVA variants for the Mg 2+ and CAT charges, which means the convergence behavior is reflected in the 16-residue QM region results. However, for SAM there are significant differences between the variants. The standard as well as all vac and cryst 16-residue results represent the charge convergence for medium-sized QM regions up to 22 residues, but are about 0.2e lower than the best estimate. In contrast, especially the active but also the no lig charges are much closer to the best estimate because important SAM-coordinating residues are already included from the beginning and do not have to be detected by PCVA. Consequently, including active site residues into the minimal QM Regarding the reaction energy (Fig. ), vac, vac fix, and cryst fix deliver results similar to standard PCVA at about -17 kcal/mol, which is about 6 kcal/mol below the best estimate (-10.5 kcal/mol) but agrees reasonably with the large QM region regime (e.g.