Is ion channel selectivity mediated by confined water?

TL;DR

This study uses molecular dynamics simulations to reveal that confined water within ion channels plays an active role in determining ion selectivity, especially influencing the position of Na+ ions.

Contribution

It uncovers the active role of confined water in ion selectivity, a previously underappreciated factor in channel function.

Findings

Confined water stabilizes Na+ in a specific position within the channel.

Absence of confined water results in identical ion positions.

Confined water interacts electrostatically and via hydrogen bonds with Na+.

Abstract

Ion channels form pores across the lipid bilayer, selectively allowing inorganic ions to cross the membrane down their electrochemical gradient. While the study of ion desolvation free-energies have attracted much attention, the role of water inside the pore is less clear. Here, molecular dynamics simulations of a reduced model of the KcsA selectivity filter indicate that the equilibrium position of Na+, but not of K+, is strongly influenced by confined water. The latter forms a stable complex with Na+, moving the equilibrium position of the ion to the plane of the backbone carbonyls. Almost at the centre of the binding site, the water molecule is trapped by favorable electrostatic interactions and backbone hydrogen-bonds. In the absence of confined water the equilibrium position of both Na+ and K+ is identical. Our observations strongly suggest a previously unnoticed active role of confined water in the selectivity mechanism of ion channels.