In previous work, MBE(n) has been successfully applied to enzymatic thermochemistry with all of the aforementioned caveats. Inclusion of ionic residues required low-dielectric boundary conditions to eliminate spurious many-body effects, which is likely a consequence of delocalization error in DFT, as discussed elsewhere. The present work extends the thermochemical protocols developed in Ref. 25 to the case of protein-ligand binding. We introduce a set of four T4-lysozyme complexes with small aromatic ligands and four other complexes with large ligands. These systems are then used to assess both the accuracy and the cost of various fragment-based methods to compute ∆E int .