All these seven different saaPCVA calculations were performed according to the established protocol (see Fig. ) and evaluated in the same way assessing sensitivities and indicators for each amino acid (see Figs. ). Here, it is important to mention that residues already included in the minimal QM region (for no lig and active) are not considered in the sensitivity and indicator calculation. Additionally, these residues are always included in the construction of atom-economical 16-residue QM regions. The compositions an equilibrated structure in water. We compare the 16-residue QM regions constructed using the newly introduced variants to the QM regions of increasing size constructed by the standard saaPCVA approach as applied in Ref. 17 (see Fig. and) to evaluate their performance.