For all proteins, the protonation state is chosen for a realistic pH value (see Sect. 4), resulting in several charged side chains. In these cases, the quantum-chemical calculations for the amino acid fragments do not converge in many cases, unless a continuum solvation model is employed to stabilized the charged amino acid side chains . Here, we employ both a dielectric constant of ε = 4 for the COSMO solvation model (as recommended in Ref. ) and a dielectric constant of ε = 78.39 (corresponding to water). For the ligands carrying multiple negative charges in 1AAL and 1A6F, a dielectric constant of ε = 4 is not sufficient to avoid convergence problems for the fragment-ligand dimers and for fragment-fragment-ligand trimers. In these two cases, MFCC and MFCC-MBE(2) results could only be obtained when using the dielectric constant for water. In all our calculations, we do not apply a distance cutoff in the MFCC part, i.e., the interactions of all fragments and caps with the ligands are included explicitly.