where δ i E QM/MM is the saaPCVA sensitivity found for the i-th amino acid and COM i is the center-of-mass distance between the i-the amino acid and the active center (i.e., a minimal QM region). This indication gives a higher weight to amino acids that are close to the active center. QM regions are then constructed by including a chosen number of amino acids with the highest Θ i . A flowchart of how this method is realized computationally can be found in the Supporting Information (Fig. ).