In addition to a global PCVA, we have considered a single amino acid PCVA, in which the MM charges of each amino acid residue are varied. This makes it possible to assess the contribution of each amino acid to the uncertainty in the QM/MM reaction energy, and can be used to guide the systematic construction of the QM region. By including amino acids with a high sensitivity to point charge variations in the QM region, the overall sensitivity of the QM/MM reaction energy can be reduced. Here, we devised a PCVA-based scheme for the systematic construction of the QM region.