Previously, we developed an approach for systematic QM region construction, the point charge variation analysis (PCVA). Compared to the well-investigated CSA and FSA it is computationally cheaper but equally reliable . PCVA is based on the variation of MM point charges for the amino acids and the subsequent evaluation of (reaction) energies to identify the residues with the highest electrostatic effect on the QM region. For this, only a single geometry optimization for the system including a minimal QM region (ideally substrates only) is required, followed by one single point calculation for each amino acid in the enzyme. Afterwards, the resulting sensitivities for each residue are correlated to the respective active site-residue distance, which results in an indicator ranking. Based on this ranking, an atom-economical QM region (defined at 16 residues by Kulik et al. ) can be constructed.