Figure presents the results obtained from the WISP analysis performed using residue G283 as the "source" to represent the BB-site (see Figure ) and D181 to represent the "sink", with equivalent results describing the second allosteric binding site (K197-site, see Figure ) provided in Figure . Analysis of the network close to the source shows a primary pathway of communication from G283 through M282, F280, Q288 to K197 (all residues on the α4, α6 and α7-helices of PTP1B) before the network begins to branch out. Key residues further along the network include those on the α4-helix (N193), which shows a strong coupling to Y152 on Loop 11, which is in turn coupled to the N-terminus of the WPD-loop through T177. Another branch point from K197 heads to E297 and S295 on the α7-helix and in turn to the α4-helix (A188 and F191) and then finally to the central portion of the WPD-loop (W179) and the P-loop catalytic residue R221. The observations made above are consistent with prior experimental studies on the allosteric regulation of PTP1B's WPD-loop. For example, our observation that the allosteric communication from the α7-helix is communicated through Loop 11 and then to the Nterminus of the WPD-loop is consistent with prior NMR studies. Further, NMR experiments analyzing the differences in the closed and open states identified a "hydrophobic core network" in PTP1B which showed altered chemical shifts depending on the WPD-loop state, this network included residues F280, Y152, F191, Y152, W179, all of which were found on our pathway. Our WISP analysis also shows many of the edges (interactions) in the network are between side chains, meaning they could be modified by natural or artificial evolution, making them potential targets for protein engineering. These results are interesting to consider, given that the standard way to perform WISP is to generate a dynamic cross correlation matrix (DCCM), using the Cα-Cα distances between residues, which may not be able to capture such relationships. Finally, we note that we have so far used a more qualitative approach to label the key residues and interactions along the allosteric network (i.e., by examining Figure and); however, the node degeneracy plots shown in Figure can be used instead, if a more quantitative approach is desired.