For protein-ligand systems, we have demonstrated that two-body interaction terms ∆E IJ , computed using the semi-empirical HF-3c method, correlate very well with results from high-quality DFT calculations (e.g., ωB97X-V/def2-ma-QZVP). The two-body terms vary significantly in both magnitude and sign, and provide a means to generate QM models in a well-defined way. A threshold τ 2B = 2.5 × 10 -4 E h offers a good balance between accuracy and computational efficiency. This is perhaps the most reliable algorithm for QM model construction of the ones examined here.