Selectivity through ion modulated changes in pKa values.

Abstract

In bacterial voltage gated sodium (Nav) channels, the passage of ions through the pore is controlled by a selectivity filter (SF) comprised of four glutamate residues. The mechanism of selectivity has been the subject of intense research, with suggested mechanisms based on steric effects, and ion triggered conformational change. Here we propose a novel mechanism based on ion-triggered shift in pKa values of SF glutamates. We study the NavMs channel for which the open channel structure is available. Our free energy calculations based on molecular dynamics simulations suggest that pKa values of the four glutamates are higher in solution of K+ ions, than in solution of Na+ ions. Since pKa values are close to the physiological pH, this results in predominant population of the fully deprotonated state of glutamates in Na+ solution, while protonated states are predominantly populated in K+ solution. Through molecular dynamics simulations we also calculate the conductances of the relevant protonation states. The deprotonated state is the most conductive, single protonated state is less conductive, and double protonated state has further reduced conductance. Thus, we propose that the selectivity is achieved through ion triggered shift in protonation state which favors more conductive states for Na+ ions and less conductive states for K+ ions. This mechanism would also suggest pH dependence of selectivity, which was experimentally observed in structurally similar NaChBas channels.