For MBE(2)-DFT calculations with ωB97X-V, the best QM models constructed in this way achieve a fidelity of 1-2 kcal/mol in triple-or quadruple-ζ basis sets, as compared to MBE(2)-DFT calculations on larger, converged models of the protein. The combination of fast semi-empirical MBE(2) calculations, used to test convergence of ∆E int with respect to model size, and convergent MBE(n) protocols for evaluating ∆E int , 14 represents a powerful tool chain for quantum-chemical studies of drug-protein interactions. The same semi-empirical model-building and convergence tests should also be useful for studies of enzyme thermochemistry and kinetics, for which we have also reported convergent MBE(n) protocols. Chem, although other electronic structure engines can also be used. A trial license for Q-Chem can be obtained from . The rinrus software is available at the URL in Ref. 49. Coordinates for the protein-ligand complexes are provided in the Supporting Information.