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Conductance selectivity of Na+ across the K+ channel via Na+ trapped in a tortuous trajectory

Significance Ion selectivity is a fundamental property of ion channels. Potassium channels exhibit an unusual selectivity, allowing passage of larger K+ ions (ionic radius of 1.3 Å) over smaller Na+ ions (1.0 Å); the mechanism underlying the small ion rejecting selectivity remains unknown. Here, we applied Na+ as a probe for examining the pore of a prototypical potassium channel and found slight Na+ conduction across the pore. Na+ traced a tortuous trajectory in the narrow pore, with multiple Na+ ions trapped here and there, leading to slow elution. Contrarily, K+ passed straight, with three ions moving together rapidly. Na+ and K+ take different paths and interactions in the pore, which creates dramatic contrast in the conduction rates of Na+ and K+. Ion selectivity of the potassium channel is crucial for regulating electrical activity in living cells; however, the mechanism underlying the potassium channel selectivity that favors large K+ over small Na+ remains unclear. Generally, Na+ is not completely excluded from permeation through potassium channels. Herein, the distinct nature of Na+ conduction through the prototypical KcsA potassium channel was examined. Single-channel current recordings revealed that, at a high Na+ concentration (200 mM), the channel was blocked by Na+, and this blocking was relieved at high membrane potentials, suggesting the passage of Na+ across the channel. At a 2,000 mM Na+ concentration, single-channel Na+ conductance was measured as one-eightieth of the K+ conductance, indicating that the selectivity filter allows substantial conduit of Na+. Molecular dynamics simulations revealed unprecedented atomic trajectories of Na+ permeation. In the selectivity filter having a series of carbonyl oxygen rings, a smaller Na+ was distributed off-center in eight carbonyl oxygen-coordinated sites as well as on-center in four carbonyl oxygen-coordinated sites. This amphipathic nature of Na+ coordination yielded a continuous but tortuous path along the filter. Trapping of Na+ in many deep free energy wells in the filter caused slow elution. Conversely, K+ is conducted via a straight path, and as the number of occupied K+ ions increased to three, the concerted conduction was accelerated dramatically, generating the conductance selectivity ratio of up to 80. The selectivity filter allows accommodation of different ion species, but the ion coordination and interactions between ions render contrast conduction rates, constituting the potassium channel conductance selectivity.