For apoenzyme, the optimal number of 6 clusters was selected based on the DBI and pSF indexes. A structure for further QM:MM calculations was selected based on the following criteria: the size of the cluster (the higher the better), cluster tightness (the average distance from the centroid, the lower the better), silhouette (the higher the better), and the agreement of the Cys493 C-Cα-Cβ-Sγ dihedral angle with its median value observed during MD simulation.