Fig. 3

Spatial profile of the hydropathic density around NaV1.7’s pore. Contour map of the hydropathic density pore function, \(m^{(0)}({\mathbf{p}},l_{\alpha }({\mathbf{p}}))\), is illustrated for \({\mathbf{p}}\in P\) and \(\alpha =1,2,\ldots ,K_{\alpha }=800\). Blue- and red-colored contour domains represent hydrophobic and hydrophilic domains around the pore, respectively. Black lines \(R({\mathbf{p}})\), \(D({\mathbf{p}})\) and \(L({\mathbf{p}})\) indicate geometrical pore characteristics (see “Methods” section). Magenta dashed line \(\nu ({\mathbf{p}})\) depicts the scales at which the PMs-VSs spatial transition takes place. Dashed black lines \(s({\mathbf{p}})\), \(\xi ({\mathbf{p}})\) and \(o({\mathbf{p}})\) account for the boundaries among subsequent atom-packing domains (see “Methods” section). Zero-crossing points of \(m^{(0)}({\mathbf{p}},l_{\alpha }({\mathbf{p}}))\) collected in \(\Omega ^{(0)}\) define HP’s boundary, i.e., the boundary between HP-forming domains \(T_{1}^{(0)}\) and \(T_{2}^{(0)}\), and hydrophilic domain \(T_{3}^{(0)}\) (see Additional file 1: S4 for calculation of zero-crossing points and construction of \(\Omega ^{(0)}\)). Black arrows \(\mathrm{[a]}\), \(\mathrm{[b]}\), and \(\mathrm{[c]}\) highlight domain boundaries. Two sets of missense SCN9A-gene mutation sites are employed; a pain-related set containing IEM, PPD and SFN mutation sites, and a neutral set containing mutation sites which are not expected to associate with pain disease phenotypes (Additional file 1: S8). Mutation sites highlighted in red color correspond to misclassified events (classification criterion; median distance from HP’s boundary (see Additional file 1: S9a)). Grey-shaded areas “a1”, “a2”, and “a3” highlight contour map regions where the number of mutation sites maximizes, i.e., mutation sites occupancy rates maximize. ES, SF, CC, AG, and IS labels mark the locations of the extracellular side, of the selectivity filter, of the central cavity, of the activation gate, and of the intracellular side, respectively