representative discussions on protein flexibility in Refs. ). Thus, crystal structure geometries should not be considered as an ultimate source of structural information on the systems at hand (this fact seems to have been overlooked in recent research efforts). We will therefore mostly restrict our discussion to particular spatial organizations of the relevant amino acid dimers/clusters, chosen to represent "upper bounds" for said interactions. In such manner, we would be able to use statistical inference tools and critically answer whether said substitutions actually lead to a substantial, potential increase in interaction energies -or, perhaps, suggest that their implications are not quite as straightforward. Still, and in order to compare our results with those of Morse et. al., we will also consider geometries derived directly from the crystal structure in Ref. Since some recent/contemporary research ventures have involved indirect assessments of the aforementioned noncovalent binding factors by means of classical molecular mechanics force fields, we shall also compare our electronic-structure-based energetics with ones obtained using the widely-applicable MMFF94 force-field -which has been specifically parametrized for van der Waals (vdW) interactions and is often used for investigations of organic molecules and polypeptides. Computational Methods Electronic structure calculations were performed using the Gaussian16 26 software suite and ran on the Faculty of Chemistry HPC cluster at the Weizmann institute of science. The B3LYP functional, which was recommended for biochemically-relevant noncovalent systems in Ref. , as well as Grimme's DFT-D3 atom-pairwise dispersion corrections and the TZVP basis set were used throughout.