were already protonated and were not altered. PDB files of all protonated structures used in the calculated presented here are available in the associated data set The productive runs (calculation of MFCC interaction energies, MFCC-MBE(2) interaction energies, and reference calculations of the interaction energies using the full systems) were performed as using density-functional theory (DFT) calculations with the AMS/ADF program package . We employed the BLYP exchange-correlation functional in combination with a DZP basis set throughout . Note that for the purpose of assessing the accuracy of the MFCC and MFCC-MBE(2) protein-ligand interaction energies compared to full, supermolecular calculations we did not include a dispersion correction. Dispersion corrections commonly applied in combination with DFT only depend on the molecular structure and, therefore, the neglect of a dispersion correction does not alter the comparison of the total energies. In all quantumchemical calculations, we applied the COSMO continuum solvation model as implemented in AMS/ADF.