To further verify these observations, we constructed atomeconomical 16-residue QM regions based on the three centrality rankings by including the corresponding highest-ranked residues and performed QM/MM calculations analogous to the previous assessment of the atom-economical PCVA-constructed QM re- gions . Since d-centrality often assigns the same value to more than one residue, in this case, the QM region contains 17 residues to cover all equally-ranked residues. The different QM regions are visualized at the bottom of Fig. , and their composition is listed in the Supporting Information in Table . Comparisons to previous PCVA results concerning QM/MM reaction energies and VDD ligand charges are shown in Fig. . Here, it emerges that the b-centrality performs much better than the dor e-centrality. The reaction energy (Fig. ) using the bcentrality (about -13.5 kcal/mol) is closer to the best estimate at -10.5 kcal/mol than for the d-centrality (-4 kcal/mol) and the e-centrality (-7 kcal/mol). Regarding VDD charges (Fig. ), the atom-economical QM region constructed based on the bcentrality is able to reproduce the best estimate charges for Mg 2+ and CAT, similar to PCVA. In contrast, the QM regions based on the dand e-centrality assign an about 0.2 higher charge for Mg and CAT compared to the best estimate. Regarding the VDD charge of the SAM ligand, none of the methods is able to assign a charge near to the best estimate, as previously observed for PCVA 20 . Nevertheless, using the b-centrality ranking pushes the charge from around zero to a positive charge of about 0.6, indicating the ability to detect SAM-impacting residues, even though the charge is overestimated here. Overall, the b-centrality seems to be the most promising centrality descriptor for QM region construction.