A barrier model of R666G cation permeation. In the proposed model, accessibility of the R666G gating pore is due to voltage-dependent movement of the DIIS4 voltage sensor as depicted schematically in A. At hyperpolarized voltages favoring inward gating charge movement, the gating pore is accessible for cation binding and permeation, whereas outward movement of gating charges favored by membrane depolarization occludes the permeation pathway. The permeation pathway was modeled as a free-energy barrier profile calculated using Eyring rate theory. Profiles at 0 mV (top panel) and −100 mV (bottom panel) membrane potential of the proposed ion permeation pathway through the R666G gating pore are depicted in B. The black and red lines represent the proposed barrier profiles encountered by K⁺ and Na⁺, respectively. The shallow voltage dependence of the I-V relation at negative potentials (Fig. 2 A) is accounted for by a barrier model with a cation binding site that is very near the external face of the electrical field (δ = 0.03). Proposed transition rate constants for K⁺ and Na⁺ over the external and internal energy barriers at 0 mV are listed in Table I.