We tested several low-level supersystem corrections in combination with four different target levels of DFT, for the activation energy in COMT. Errors with respect to the target level of DFT (applied to the entire enzymesubstrate model) are illustrated in Fig. and numerical valuess for each supersystem correction can be found in Table . The low-level methods that we tested include the semi-empirical thrice-corrected methods HF-3c and PBEh-3c, which use a minimal and a double-ζ basis set, respectively. We also tested Hartree-Fock (HF) theory and the functional LRC-ωPBEh, both with the 6-31G basis set. Note that 6-31G is much less expensive than other double-ζ basis sets, if the electronic structure software can take advantage of compound sp shells. For this particular 632-atom enzyme-substrate complex, all four of these supersystem corrections require similar computational time, which constitutes less than 20% overhead on top of a MBE(2) calculation.