The system used to test further PCVA schemes is the catechol O-methyltransferase (COMT) , which was also targeted in the work of Kulik and co-workers regarding systematic QM region determination and in our previous work on PCVA . The structural monomer model, which is based on the crystal structure (PDB: 3BWM) and processed as described in Section 6, contains the neutral S -adenosyl methionine (SAM), the catecholate anion (CAT), and the catalytically active Mg 2+ (see Fig. ). These three ligands also represent the minimal QM region used in saaPCVA originally, while in the assessment of larger QM regions a water molecule close to Mg 2+ is additionally considered (see Fig. ).