A dielectric constant in the range ε = 2-4 is often used to represent the hydrophobic interior of a protein. In previous work, we found that a continuum solvation model with ε ≈ 4 helps to avoid spurious oscillations in MBE(n) calculations, even for protein models with numerous charged residues where MBE(n) with vacuum boundary conditions does oscillate. All calculations reported here use the conductor-like polarizable continuum model (C-PCM) with ε = 4. The interface with the continuum region is represented using a van der Waals cavity, 106 constructed from atomic radii that are 1.2× larger than values in the modified Bondi set, 106,107 then discretized using the switching/Gaussian procedure. 105,108-110 For ωB97X-V calculations, 110 Lebedev points were used for hydrogen and 194 points for other nuclei. For HF-3c, we used 50 points for hydrogen and 110 points for other nuclei. For supersystem calculations involving the entire protein, a conjugate gradient implementation of C-PCM was used. 3 Results and Discussion 3.1. T4 Lysozyme Data Set. The primary goal of this work is to develop reliable and reproducible protocols that afford energetically converged protein-ligand models that are usable across different levels of electronic structure theory. In the present work, we use HF-3c to test convergence with respect to model size but we demonstrate ∆E int calculations using ωB97X-V in basis sets up 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 in conjunction with either the def2-ma-SVP basis set (labeled "DZ" in the figure) or else the the def2-ma-TZVP basis set ("TZ").