We built two models describing the differences in the interactions between the closed and open WPD-loop conformations using two different approaches, the Jensen-Shannon distance (JS-distance) and the mutual information (MI), see the Methodology section. As would be expected given that the two metrics are highly related, the MI and JS-Distance calculations gave highly similar results, with an R 2 of 0.82 when comparing their per residue scores (Figure ), Further, of the top 50 residues identified using both methods, 45 of these residues are shared among both lists. For this reason, we focused the remainder of our analysis on only one of these approaches, the JS-Distance, which is summarized in Figure . Our approach using the JS-Distance 78 was able to capture both the local and several distal interactions which are associated with the WPD-loop's conformational state (Figure and). Analysis of Figure shows several residues identified as important for regulating the WPD-loop conformation located around the two known allosteric drug binding sites, alongside important residues found on or around residues with mutations that are known to alter the kcat or KM of PTP1B by ≥50%. We used a helper function available within our package to calculate each residue's minimum heavy atom distance from the catalytic WPD-loop residue D181 and compared this to the obtained per residue scores (Figure ). Whilst unsurprisingly some of the residues closest to D181 have the largest score, our analysis highlights several residues that have both a relatively high score and a relatively large distance to D181, suggesting our method can capture both the local and allosteric interactions which regulate the WPD-loop. This is further backed up by the weak linear correlation between the per residue scores and the distance to D181 (R 2 = 0.24). Those residues that are relatively distal from D181 but our found by our model to have a significant impact on the WPD-loop are labeled in Figure , and include residues on the α4, α6 and α7-helices (residues 189-201, 263-282 and 285-298 respectively) and Loop 11 (residues 149-154), which have all previously been identified as part of PTP1B's allosteric network.