The PCVA-based construction of the QM region is limited to the electrostatic effect of the amino acids and thereby lacking other properties which may also play an important role in QM region determination. Therefore, it is possible that crucial residues (e.g. catalytically important) may be absent under the detected residues. Here, the biochemical and structural understanding should be considered as well when constructing QM regions. Altogether, we suppose that our fast and computationally cheap approach is a good complement to existing methods for the automatic and systematic QM region construction. We expect that future developments concerning uncertainty quantification for QM/MM calculation will also allow for the development of more sophisticated schemes for the systematic construction of QM