Cooperation of Hydrophobic Gating, Knock-on Effect, and Ion Binding Determines Ion Selectivity in the p7 Channel

Ion channels selectively allow certain ions to pass through at much higher rates than others, and thereby modulate ionic concentrations across cell membranes. The current molecular dynamics study elucidates the intricate mechanisms that render ion selectivity to the viral channel p7 by employing free energy calculations. Free energy barriers of 5.4 and 19.4 kcal mol(-1) for K+ and Ca2+, respectively, explain the selectivity of the channel reported in experiments. Initially, the permeating ions encounter a hydrophobic barrier followed by stabilization in an ion-binding site. Electrostatic repulsion between the permeating ions propels one of the ions out of the binding site to complete the process of permeation. K+ and Ca2+ are seen to exhibit different modes of binding toward a ring of asparagine residues, which serves as the binding site. The findings illustrate how the overall selectivity of a channel can be achieved by a combination of subtle differences.