Naively, it could be expected that residues closer to the active site show higher sensitivities to point charge variations than distant ones. However, there are also several high-sensitivity amino acids at medium distances to the active site and low-sensitivity residues very close to the substrates. This observation confirms that an exclusively distance-based approach to include residues into the QM region is not able to detect all important amino acids and furthermore includes residues which are probably not necessary to obtain consistent QM regions. To find a compromise between including amino acids that show a high sensitivity and those that are close to the active site, we define an empirical QM region indicator Θ i for each amino acid by dividing the sensitivity by the COM distance between the amino acid and the active site, i.e.,