In general, we showed that performing saaPCVA in a system without water molecules and furthermore with starting by directly optimizing a crystal structure without previous processing delivers reasonable results. This makes the already simple standard saaPCVA approach for constructing QM regions more easily applicable. Our results indicate that it is crucial to include the substrates in the minimal QM region that is used as basis of saaPCVA. In addition to that, extra active site residues may be included to improve the results especially concerning consistent ligand charges. Nevertheless, the application of saaPCVA with a minimal, substrates-only QM region delivers results with sufficient accuracy if the extension of the QM region is not applicable due to computational restrictions or if there is no reliable reference for the active site residues to be included.