To further ensure the applicability of the centrality-based and hybrid methods, we additionally applied the identical procedure to the triosephosphate isomerase (TIM), which was also subject to our previous investigations . These results are shown and discussed in Section S3 of the Supporting Information and confirm the general trends observed for COMT, even though the agreement for the QM/MM calculations using a 16-residue, atomeconomical QM region with the best estimate is worse.