Abstract
The ability of biological ion channels to conduct selected ions across cell membranes is critical for the survival of both animal and bacterial cells. Numerous investigations of ion selectivity have been conducted over more than 50 years, yet the mechanisms whereby the channels select certain ions and reject others are not well understood. Here we report a new application of Jarzynski’s Equality to investigate the mechanism of ion selectivity using non-equilibrium molecular dynamics simulations of Na+ and K+ ions moving through the KcsA channel. The simulations show that the selectivity filter of KcsA adapts and responds to the presence of the ions with structural rearrangements that are different for Na+ and K+. These structural rearrangements facilitate entry of K+ ions into the selectivity filter and permeation through the channel, and rejection of Na+ ions. A mechanistic model of ion selectivity by this channel based on the results of the simulations relates the structural rearrangement of the selectivity filter to the differential dehydration of ions and multiple-ion occupancy and describes a mechanism to efficiently select and conduct K+. Estimates of the K+/Na+ selectivity ratio and steady state ion conductance for KcsA from the simulations are in good quantitative agreement with experimental measurements. This model also accurately describes experimental observations of channel block by cytoplasmic Na+ ions, the “punch through” relief of channel block by cytoplasmic positive voltages, and is consistent with the knock-on mechanism of ion permeation.
Highlights
Steady state concentration differences for inorganic ions between the cytoplasm and the extracellular bathing solution are essential for cell viability
These structures show that the K+ ions are dehydrated when they are located within the selectivity filter of the channel, and it is likely that the process of dehydration of the ions is important to the mechanism of ion selectivity [2]
Single Na+ or K+ ions were pulled through the channel in these simulations in order to simulate the interactions between the individual ions and the protein, the structure of the KcsA channel used was obtained at high K+ concentration, and represents the structure of the channel when the selectivity filter is occupied by multiple ions
Summary
Steady state concentration differences for inorganic ions between the cytoplasm and the extracellular bathing solution are essential for cell viability. The mechanism of ion selectivity by ion channels has been most intensively studied in K+-selective channels because of the availability of several atomic resolution protein structures of these channels These structures show that the K+ ions are dehydrated when they are located within the selectivity filter of the channel, and it is likely that the process of dehydration of the ions is important to the mechanism of ion selectivity [2]. It was suggested by Bezanilla and Armstrong in 1972 that the mechanisms of ion selectivity would emphasize either selective binding of the ions in the selectivity filter of the channel or selective exclusion of ions from the selectivity filter [3]. Multiple binding sites for ions in the selectivity filter have been suggested to be necessary for a high throughput flux of K+ [4,5,6,7,8,9,10], but how they are linked with the ion selectivity is still under debate [11,12,13,14,15]
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