In the end, we find that enzymatic thermochemistry can be reproduced with sub-kcal/mol fidelity using practical protocols based on fragmentation. The stage is now set to push the accuracy of these calculations beyond the DFT level, by means of hybrid methods that deploy high-level methods for the two-body interactions combined with three-body DFT to capture polarization by the environment. We are also exploring the use of fragment-based vibrational frequency calculations, as pioneered by others, to include zero-point corrections and finite-temperature thermal corrections. (The use of smooth cutoffs in gradient calculations has already been demonstrated. ) Network analysis can be used to build sensible (if sizable) models of the enzyme-substrate complex, 52,100,101 and then the protocols developed here can provide converged results for any given model. Together, these developments promise to make QC modeling of enzymatic reactions more robust and systematic.