Ion-triggered selectivity in bacterial sodium channels

Abstract

<p id="d1912447e167">Voltage-gated Na ⁺ channels are essential components of the cell membrane in any realm of life. To perform their biological functions, Na ⁺ channels need to conduct Na ⁺ at high rates, while blocking K ⁺. Molecular dynamics simulations showed that the selectivity filter of bacterial Na ⁺ channels is a highly flexible structure. This feature favors fast Na ⁺ conduction. However, it is still unknown how such highly flexible structure is able to select Na ⁺ over K ⁺. In this contribution, we show that in the presence of K ⁺, the selectivity filter switches to a nonconductive state. The effect of K ⁺ on the dynamics of Na ⁺ channels explains how these proteins can be contemporarily highly permeable to some ion species and highly selective for similar ones. </p><p class="first" id="d1912447e204">Since the availability of the first crystal structure of a bacterial Na ⁺ channel in 2011, understanding selectivity across this family of membrane proteins has been the subject of intense research efforts. Initially, free energy calculations based on molecular dynamics simulations revealed that although sodium ions can easily permeate the channel with their first hydration shell almost intact, the selectivity filter is too narrow for efficient conduction of hydrated potassium ions. This steric view of selectivity was subsequently questioned by microsecond atomic trajectories, which proved that the selectivity filter appears to the permeating ions as a highly degenerate, liquid-like environment. Although this liquid-like environment looks optimal for rapid conduction of Na ⁺, it seems incompatible with efficient discrimination between similar ion species, such as Na ⁺ and K ⁺, through steric effects. Here extensive molecular dynamics simulations, combined with Markov state model analyses, reveal that at positive membrane potentials, potassium ions trigger a conformational change of the selectivity toward a nonconductive metastable state. It is this transition of the selectivity filter, and not steric effects, that prevents the outward flux of K ⁺ at positive membrane potentials. This description of selectivity, triggered by the nature of the permeating ions, might have implications on the current understanding of how ion channels, and in particular bacterial Na ⁺ channels, operate at the atomic scale. </p>