Despite their importance across species, our understanding of Na v s remains limited due to their larger size, structural flexibility and multi-step process. Over the years, mechanistic insights of Na v s conduction, ion binding, selectivity and gating processes were gathered from experimental characterization techniques such as electrophysiological measurements, Fourier transform and two-dimensional infrared spectroscopy, X-ray crystallography, electron paramagnetic resonance, fluorescence, nuclear magnetic resonance, mutagenesis and others. Computational studies feature continuum or molecular dynamics (MD) approaches, often focusing on smaller, bacterial, cation or water channels. Although conducted on other types of channels, these studies emphasize the importance of electrostatics with explicit polarization effects, and water interactions when modeling ion transport through proteins. More specifically, Bichet et al. showed that the selectivity of Kir3.2 was affected by the charges of cavity-facing residues below the selectivity filter, regardless of their position. Nimigean et al. increased the conductance of KcsA four-fold by altering the charge at the channel's intracellular mouth. Further electrostatic effects in ion channels were observed through the alignment of water molecules in the pore. For example, pore waters in KcsA were found to be partially aligned, forming a large electric dipole. Similarly, other simulations of the calcium release-activated calcium channel demonstrated that a change in the protein electrostatic field will increase the number of pore waters and tune their orientation, regulating ion permeation. Figure . a) Ions permeate through the pore domain (PD), made from helices S5-S6 of DI, DII, DIII, and DIV. Helices S1-S4 make the voltage-sensing domains (VSD). S4 and its gating charge residues triggers state transitions in response to changes in the transmembrane potential. b) Domain-swapped conformation of Na v 1.7 (PDB ID:6J8I ). The pore is lined with important residues, including Asp-361 (DI), Glu-927 (DII), Lys-1406 (DIII) and Ala-1698 (DIV) that make the selectivity filter; and Leu-398 (DI), Leu-964 (DII), Ile-1453 (DIII) and Tyr-1755 (DIV) that make the intracellular gate.