The crystal structure of COMT (PDB code: 3BMW) was protonated using the H++ web server 102 at pH = 7.0, salinity of 0.15 M, ε in = 10, and ε out = 80. Ligand atoms were protonated separately using Py-MOL, then validated against reactant and product structures taken from Ref. 14. As in that work, the inhibitor 3,5-dinitrocatechol in the crystal structure was re-placed with catecholate (C 6 H 5 O - 2 ). Reactant and product structures were relaxed using the GFN2-xTB semiempirical model 103 with a generalized Born/surface area (GBSA) implicit solvent model for water. 104 GFN2-xTB with implicit solvent has been recently benchmarked for protein structure, with results that compare well to experiment. To obtain the transition state, we scanned the bond length between the sulfur atom on SAM and the transferred methyl group. The system was then trimmed to obtain the 632-atom "model 8" from Ref. 14, which contains residues within a 5 Å radius of active site along with three important residues identified experimentally. This model affords converged energetics with respect to larger models. For AspDC (PDB code: 1UHE), 106 a single monomer unit can be directly downloaded from the protein database although the complete structure is an octamer. Starting from the latter, a large radial cutoff of 12 Å was used for structure relaxation using GFN2-xTB in implicit solvent. From that relaxed structure, a smaller 5 Å region was created for a scan along the bond-breaking coordinate, and from that scan a transition state and a product structure were selected. For fragmentation calculations, the negatively charged ligand and the cationic arginine residue coordinated to it were included in a single fragment, such that all fragments are uncharged.