The resulting indicator is plotted in Fig. . A comparison of the indicators for the schemes PCVA-A to PCVA-D is shown in the Supporting Information (Fig. ), and an additional Table lists the 16 amino acid residues with the highest QM region indicators for the schemes PCVA-A to PCVA-E (see also Section 7). When using the QM-only instead of the full QM/MM reaction energy (i.e., comparing PCVA-A and PCVA-B), the only change among the highest-ranked amino acids is that ILE88 is replaced by CYS68. Similarly, only two changes among the 16 amino acids with the highest indicators are found when using the reactant instead of the product energies (i.e., comparing PCVA-C and PCVA-D). Here, LEU64 and TRP142 are replaced by VAL41 and CYS172. All these amino acids show very similar sensitivities and indicators in the different schemes. Larger differences are found going form the reaction energies (PCVA-B) to using the reactant energies (PCVA-D), where six differences appear among the top-16 amino acids. However, these changes mostly occur for amino acids with very close values of the QM region indicator. Furthermore, the use of the reactant or product energies avoids error cancelation that might be present when using the reaction energy. Finally, only two differences (VAL41 and TYR67 instead of LEU64 and TYR146) are found among the 16 highest-ranked amino acids when going to a simplified numerical differentiation formula (i.e., from PCVA-D to PCVA-E). Overall, this confirms that the PCVA-E approximation seems to be a reasonable choice.