Since standard saaPCVA worked well for COMT compared to computationally more expensive methods such as CSA and FSA, we tested several variations and further simplifications for this system. It turned out that starting saaPCVA directly from a protein crystal structure in vacuum without pre-processing delivers equally reasonable results compared to the standard PCVA variant. Moreover, we showed that it can be beneficial to include several important active site residues to the minimal QM region prior to saaPCVA. In general, if the additional computational cost is considered to be reasonable and if there is clarity about the important active site residues we recommend to include these amino acids in the QM region which is then used for saaPCVA.