Overall, we have shown that protein network centralities, in particular the betweenness centrality, are a promising descriptor for the systematic construction of QM regions. The bcentrality allows one to identify residues that have important non-electrostatic or allosteric effects on the active site, and that are thus missed by descriptors that only consider the direct, electrostatic effect, such as our previously developed PCVA scheme. Therefore, we propose to augment QM regions constructed using PCVA with residues that have a high b-centrality, for which two simple schemes have been proposed.