Selectivity and Permeation of Alkali Metal Ions in K+-channels

Furini, Simone; Domene, Carmen

doi:10.1016/j.jmb.2011.04.043

Cited by 33 publications

(36 citation statements)

References 47 publications

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“…51 Finally, the apparent stability of the three-ion configuration KwKwK suggests that four-ion knock-on mechanisms may exist, as has been suggested for KirBac1.1. 21 …”

Section: Discussionmentioning

confidence: 99%

Energetics of Multi-Ion Conduction Pathways in Potassium Ion Channels

Fowler

Abad

Beckstein

et al. 2013

J. Chem. Theory Comput.

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Potassium ion channels form pores in cell membranes, allowing potassium ions through while preventing the passage of sodium ions. Despite numerous high-resolution structures, it is not yet possible to relate their structure to their single molecule function other than at a qualitative level. Over the past decade, there has been a concerted effort using molecular dynamics to capture the thermodynamics and kinetics of conduction by calculating potentials of mean force (PMF). These can be used, in conjunction with the electro-diffusion theory, to predict the conductance of a specific ion channel. Here, we calculate seven independent PMFs, thereby studying the differences between two potassium ion channels, the effect of the CHARMM CMAP forcefield correction, and the sensitivity and reproducibility of the method. Thermodynamically stable ion–water configurations of the selectivity filter can be identified from all the free energy landscapes, but the heights of the kinetic barriers for potassium ions to move through the selectivity filter are, in nearly all cases, too high to predict conductances in line with experiment. This implies it is not currently feasible to predict the conductance of potassium ion channels, but other simpler channels may be more tractable.

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“…51 Finally, the apparent stability of the three-ion configuration KwKwK suggests that four-ion knock-on mechanisms may exist, as has been suggested for KirBac1.1. 21 …”

Section: Discussionmentioning

confidence: 99%

Energetics of Multi-Ion Conduction Pathways in Potassium Ion Channels

Fowler

Abad

Beckstein

et al. 2013

J. Chem. Theory Comput.

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“…The knock-on mechanism, first hypothesized in the fifties by Hodgkin and Keynes [10], was described at atomic detail by computational studies [11], [12], and free-energy calculations revealed energy barriers of the order of 2–4 kcal/mol for the concerted motion of three K + ions through the filter of K + -channels [13], [14], [15]. These free-energy barriers along a multi-ion permeation pathway were shown to increase if one of the permeating ions was Na + instead of K + , offering some insight about selectivity in K + -channels [16], [17], [18]. The recent crystal structure of a prokaryotic voltage gated sodium channel NavAb from Arcobacter butzleri in combination with all-atom MD simulations can also provide important information concerning conduction and selectivity in Na + -channels.…”

Section: Introductionmentioning

confidence: 97%

On Conduction in a Bacterial Sodium Channel

2012

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Voltage-gated Na+-channels are transmembrane proteins that are responsible for the fast depolarizing phase of the action potential in nerve and muscular cells. Selective permeability of Na+ over Ca2+ or K+ ions is essential for the biological function of Na+-channels. After the emergence of the first high-resolution structure of a Na+-channel, an anionic coordination site was proposed to confer Na+ selectivity through partial dehydration of Na+ via its direct interaction with conserved glutamate side chains. By combining molecular dynamics simulations and free-energy calculations, a low-energy permeation pathway for Na+ ion translocation through the selectivity filter of the recently determined crystal structure of a prokaryotic sodium channel from Arcobacter butzleri is characterised. The picture that emerges is that of a pore preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers. In contrast to K+-channels, the movements of the ions appear to be weakly coupled in Na+-channels. When the free-energy maps for Na+ and K+ ions are compared, a selective site is characterised in the narrowest region of the filter, where a hydrated Na+ ion, and not a hydrated K+ ion, is energetically stable.

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“…MD simulations of ion selectivity in the bacterial KcsA K + -selective channel have identified numerous parameters of the ion-protein interaction such as ligand field strength, coordination geometry or number, or the surrounding protein matrix, that are important factors for determining ion selectivity [9], [12], [15], [17]–[21]. These methods used in MD simulations are powerful approaches that can provide insight into selectivity mechanisms from free-energy barriers; however, they usually employ constraints or algorithms to achieve fast sampling of rare trajectories that are not readily available in straightforward molecular dynamics simulations.…”

Section: Introductionmentioning

confidence: 99%

Non-Equilibrium Dynamics Contribute to Ion Selectivity in the KcsA Channel

et al. 2014

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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.

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Selectivity and Permeation of Alkali Metal Ions in K+-channels

Cited by 33 publications

References 47 publications

Energetics of Multi-Ion Conduction Pathways in Potassium Ion Channels

Energetics of Multi-Ion Conduction Pathways in Potassium Ion Channels

On Conduction in a Bacterial Sodium Channel

Non-Equilibrium Dynamics Contribute to Ion Selectivity in the KcsA Channel

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