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

Abstract

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 Ca(2+), 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 Ca(2+) 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.

Urea–Aromatic Stacking and Concerted Urea Transport: Conserved Mechanisms in Urea Transporters Revealed by Molecular Dynamics

“…In this configuration, the NH 2 groups of the two molecules are close together (visual inspection), so that there is electrostatic repulsion between them. This repulsion drives the transition from intermediate III to intermediate IV, and such repulsion is reminiscent of the knock-on phenomenon seen in ion transport. , There is an alternative path that could be followed to reach intermediate IV, that via intermediate IIb. In this path, however, there is a complete absence of interurea knock-on, and there is no force to drive the first urea molecule out of the selectivity filter.…”

“…The windows sampled include all configurations intermediate between the two urea molecules entering the pore from the periplasmic side, and the two molecules exiting from the cytoplasmic side. The minimum free energy path (MFEP) was calculated using an approach described previously, 26 and snapshots corresponding to important intermediates in the transport process are shown above and below the free energy landscape in the figure. Five stable configurations are identified from the free energy surface, and these are labeled I, IIa, IIb, III, and IV.…”

“…Molecular simulation studies on transport proteins have shown that, in general, channels conduct solutes at rates much faster than transporters. − UTs allow urea to pass through at very high rates that resemble channel-like behavior, rather than that of transporters. − The bacterial urea transporter dvUT from the bacterium Desulfovibrio vulgaris is an ideal system for investigating urea transport, owing to its striking structural similarity with mammalian urea transporters . Like other urea transporters, dvUT is trimeric, with three identical monomeric units that possess a narrow pore .…”

Ion Selectivity and Permeation Mechanism in a Cyclodextrin-Based Channel

“…Molecular dynamics (MD) simulations have served as an indispensable technique in characterizing ion transport through biological channels. − Early MD studies on the KcsA K + channel revealed that ion conduction through the channel is facilitated by a knock-on mechanism, whereby the movement of an ion through the channel is propelled by electrostatic repulsion from a subsequent ion entering the channel . It was later shown that the knock-on event involves fully desolvated ions .…”