We applied this approach to catechol O-methyltransferase (COMT) since it is a well-understood system regarding systematic QM region construction. The graph was constructed based on a classical MD trajectory (see Computational Details) using WISP as described above. Based on this graph, we calculated the d-, b-, and e-centralities for each single amino acid. These are visualized in Fig. , where a representation of the residue-active site center-of-mass distances is included for comparison.