Our first model system focuses on the protein-peptide binding interaction between the PSD95-PDZ3 domain with the CRIPT peptide (Figure ). The PSD95-PDZ3 domain (from now on referred to as just the PDZ3 domain) is an approximately 100 residue long protein that contains a peptide binding site for the 5 residue CRIPT peptide, with peptide binding known to allosterically modulate the PDZ3 domain. One such study on the impact of peptide binding used exhaustive single and double point mutant screening to calculate the average mutational sensitivity of each PDZ3 residue to ΔGbind, as a way to probe what residues throughout the PDZ3 domain are perturbed upon peptide binding (Figure ). This study enabled the authors to classify every PDZ3 domain residue as "orthosteric", "allosteric" or "remainder" with respect to peptide binding, based on each residues mutational sensitivity and the proximity to the peptide. We applied KIF to see if we could identify those residues on the PDZ3 domain that are sensitive to peptide binding by comparing the protein interaction networks generated from MD simulations of the PDZ3 domain with (1) the CRIPT peptide bound and (2) without the CRIPT peptide bound. To this end, we performed 10 x 100 ns long MD simulations of the PDZ3 domain in both the unliganded state and with the peptide bound, in order to generate 20,000 frames for feature generation (the non-covalent interactions) with PyContact 1 (see the Methodology section). We then classified each frame as either "Peptide Bound" or "Unliganded", simply according to whether the given frame was from the peptide bound or unliganded MD simulations. We applied both our ML and statistical modelling modules to evaluate the differences between the two classes (binary classification). (B, C) Calculated per feature (interaction) (B) and per residue (C) scores for distinguishing between the peptide bound and unliganded states of the PDZ3 domain, obtained from our statistical analysis module using the JS-Distance metric. Residues are labeled and color coded according to their definitions provided by Faure et al. For panel B, the thickness of the cylinder indicates the relative score of the feature/interaction. Cylinders are colored according to their interaction type, with red indicating a hydrogen bond, blue indicating a salt bridge, green indicating a hydrophobic interaction and pink a van der Waals interaction. For panel C, the size of the sphere represents the per residue score, and each residue is colored using the same scheme as in panel A, with the exception that some "Remainder" residues' side chains are shown and colored green if their per residue score is large considering their distance from the peptide. (D) Minimum heavy atom distance of each residue to any peptide residue against the per residue scores, as in panel C.