-17 kcal/mol). Surprisingly, the cryst PCVA energy delivers a better energy with about -13 kcal/mol compared to the best estimate. This can be a result of a specific combination of amino acids in the QM region. Including active site residues in the PCVA approach (active) leads to the best result in full agreement with the best estimate energy, which again implies improvements of this approach compared to standard. The QM region constructed by no lig PCVA delivers the worst reaction energy (about -24 kcal/mol), which indicates ligands being crucial to be included in the minimal QM region, as they affect the importance of specific residues for a consistent QM region.