Ion channel selectivity through ion- modulated changes of selectivity filter pKa values

In bacterial voltage -gated sodium channels, the passage of ions through the pore is controlled by a selectivity filter (SF) composed of four glutamate residues. The mecha-nism of selectivity has been the subject of intense research, with suggested mechanisms based on steric effects, and ion-triggered conformational change. Here, we propose an alternative mechanism based on ion-triggered shifts 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 val-ues of the four glutamates are higher in solution of K+ ions than in solution of Na+ ions. Higher pKa in the presence of K+ stems primarily from the higher population of dunked conformations of the protonated Glu sidechain, which exhibit a higher pKa shift. 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 calculate that the deprotonated state is the most conductive, the singly protonated state is less conductive, and the doubly protonated state has significantly reduced conduct-ance. Thus, we propose that a significant component of selectivity is achieved through ion-triggered shifts in the protonation state, which favors more conductive states for Na+ ions and less conductive states for K+ ions. This mechanism also suggests a strong pH dependence of selectivity, which has been experimentally observed in structurally similar NaChBac channels.