show a good agreement with an R 2 of 0.91. We found more favorable B3LYP-D3 interaction energies by 1 kcal/mol, on average (Supporting Information Figure ). Comparing gas-phase SAPT0 and SAPT2 gives an R 2 of 0.96, while the analogous DLPNO-CCSD(T) energetics gives an R 2 of 0.90 (Supporting Information Figures and). As expected, comparing SAPT0 interaction energies to solvated DLPNO-CCSD(T) energies yields a lower R 2 of 0.75, and SAPT0 interaction energies are roughly 1.5 times more favorable than DLPNO-CCSD(T) counterparts (Supporting Information Figure ). These limitations of SAPT0 primarily derive from the lack of solvent treatment to mimic the screening effect of the protein environment. Nevertheless, we use SAPT0 and F-SAPT for energetic decomposition analysis rather than DFT-based energy decomposition analysis (EDA) schemes because they recover dispersive interactions from firstprinciples and enable energetic decomposition to understand the contributions of protein functional groups (i.e., with F-SAPT, see Sec. 3b). We report total interaction energy comparisons using values computed with B3LYP-D3. It was selected for its ability to incorporate solvent and its good reproduction of solvent-environment-corrected DLPNO-CCSD(T) interaction energies.