In the smallest models, MBE(3) yields a marginally smaller interaction energy as compared to a full-system calculation but converges to the full-system result in larger models. For the largest model (619 atoms), the difference in ∆E int with respect to the full-system cal- Interaction energy ∆Eint for the benzene ligand in 1O48, computed using radial enzyme models of increasing size. Model size in number of atoms is indicated along the bottom axis while the top axis shows the radius used to generate each model. Calculations were performed using ωB97X-V with either the def2-ma-SVP basis set ("DZ") or else the def2-ma-TZVP basis set ("TZ"). MBE(n) calculations used Rcut = 8 Å. The "unfragmented" result is a conventional supramolecular calculation of ∆Eint. culation is 1.3 kcal/mol for MBE(2) and 0.4 kcal/mol for MBE(3), at the ωB97X-V/def2-ma-SVP level. If the def2-ma-TZVP basis set is used instead, the error is 1.0 kcal/mol for MBE(2) and 1.7 kcal/mol for MBE(3). Strictly speaking, MBE(3) is less accurate than MBE (2) for the largest enzyme model and basis set, but the difference with respect to MBE(2) is only a tiny fraction (< 1%) of ∆E int = -80 kcal/mol. For all practical purposes, we conclude that MBE(3) provides negligible improvement upon MBE(2) in this case. for the numerical data.) Notably, the 1MMQ and 1ZP5 systems are approximately the same size as the T4 lysozymes that were also converged by R cut = 8 Å, whereas 1BOZ is the largest system considered here, and it exhibits the slowest convergence as measured by R cut . In future studies of new enzymes, two-body screening at a semi-empirical level of theory may offer a way to test convergence at only modest cost, and this is an avenue that we are currently pursuing. Using the aforementioned system-specific R cut values, we next examine how MBE(n) converges towards the supersystem result, again using HF-3c calculations, with results up to n = 4 presented in Table . We extended these calculations to the four-body level because the two-body accuracy is inferior to what we observed for the T4-lysozyme data set. For example, in the case of 1MMQ the accuracy of MBE(2) lies outside of our strict 0.1 kcal/mol/monomer tolerance but that is rectified at the three-body level, and MBE(3) calculations also noticeably improve the result for 1O48 as well. The For 1ZP5, MBE( ) is fortuitously accuracy but MBE(3) is much worse, deviating from the full-system value of ∆E int by 29 kcal/mol. That observation, combined with the dramatic failure of MBE(2) for 1MMQ (21 kcal/mol error) hints at additional complexities for these two metalloproteins. Both systems feature Zn 2+ coordinated to the inhibitor ligand (as shown in Fig. for 1ZP5), leading to sizable many-body polarization.