Mechanism for variable selectivity and conductance in mutated NaK channels

Na ⁺ conduction has been demonstrated in a few K ⁺ channels and has been widely used to characterize the physiological selectivity and C-type inactivation in K ⁺ channels. By using molecular dynamics simulations and free-energy calculations, we found that K ⁺ and Na ⁺ have distinct preferable binding configurations in the conductive filter of two highly K ⁺ selective channels, which are mutated from the nonselective NaK channel and can conduct Na ⁺ upon removal of K ⁺. Disruption of a conserved hydrogen bond interaction between residues in the filter and the pore helices can significantly decrease the free-energy differences and barriers between the K ⁺ binding configurations, whereas it has little effect on the free-energy landscape for Na ⁺. We propose that the enhancement of the fluctuation of the filter structure decreases the affinity and conducting barrier of K ⁺ and therefore the ability of K ⁺ to block Na ⁺ currents, predominantly responsible for the reduced K ⁺ selectivity.