Dataset Information

Molecular Dynamics of Ion Conduction through the Selectivity Filter of the NaVAb Sodium Channel.

ABSTRACT: The determination of the atomic structures of voltage-gated bacterial sodium channels using X-ray crystallography has provided a first view of this family of membrane proteins. Molecular dynamics simulations offer one approach to clarify the underlying mechanism of permeation and selectivity in these channels. However, it appears that the intracellular gate of the pore domain is either closed or only open partially in the available X-ray structures. The lack of structure with a fully open intracellular gate poses a special challenge to computational studies aimed at simulating ion conduction. To circumvent this problem, we simulated a model of the NaVAb channel in which the transmembrane S5 and S6 helices of the pore domain have been truncated to provide direct open access to the intracellular entryway to the pore. Molecular dynamics simulations were carried out over a range of membrane potential and ion concentration of sodium and potassium. The simulations show that the NaVAb selectivity filter is essentially a cationic pore supporting the conduction of ions at a rate comparable to aqueous diffusion with no significant selectivity for sodium. Conductance and selectivity vary as a function of ion concentration for both cations. Permeation occurs primarily via a knock-on mechanism for both sodium and potassium, although the ion ordering in single file along the pore is not strictly maintained. The character of the outward current appears quite different from the inward current, with a buildup on ions in the selectivity filter prior to escape toward the extracellular side, indicating the presence of a rectification effect that is overcome by nonphysiological applied voltages.

SUBMITTER: Callahan KM

PROVIDER: S-EPMC6765333 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Molecular Dynamics of Ion Conduction through the Selectivity Filter of the Na<sub>V</sub>Ab Sodium Channel.

Callahan Karen M KM Roux Benoît B

The journal of physical chemistry. B 20181029 44

The determination of the atomic structures of voltage-gated bacterial sodium channels using X-ray crystallography has provided a first view of this family of membrane proteins. Molecular dynamics simulations offer one approach to clarify the underlying mechanism of permeation and selectivity in these channels. However, it appears that the intracellular gate of the pore domain is either closed or only open partially in the available X-ray structures. The lack of structure with a fully open intrac ...[more]

PMID: 30351118

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Project description:Striking structural differences between voltage-gated sodium (Nav) channels from prokaryotes (homotetramers) and eukaryotes (asymmetric, four-domain proteins) suggest the likelihood of different molecular mechanisms for common functions. For these two channel families, our data show similar selectivity sequences among alkali cations (relative permeability, Pion/PNa) and asymmetric, bi-ionic reversal potentials when the Na/K gradient is reversed. We performed coordinated experimental and computational studies, respectively, on the prokaryotic Nav channels NaChBac and NavAb. NaChBac shows an "anomalous," nonmonotonic mole-fraction dependence in the presence of certain sodium-potassium mixtures; to our knowledge, no comparable observation has been reported for eukaryotic Nav channels. NaChBac's preferential selectivity for sodium is reduced either by partial titration of its highly charged selectivity filter, when extracellular pH is lowered from 7.4 to 5.8, or by perturbation-likely steric-associated with a nominally electro-neutral substitution in the selectivity filter (E191D). Although no single molecular feature or energetic parameter appears to dominate, our atomistic simulations, based on the published NavAb crystal structure, revealed factors that may contribute to the normally observed selectivity for Na over K. These include: (a) a thermodynamic penalty to exchange one K(+) for one Na(+) in the wild-type (WT) channel, increasing the relative likelihood of Na(+) occupying the binding site; (b) a small tendency toward weaker ion binding to the selectivity filter in Na-K mixtures, consistent with the higher conductance observed with both sodium and potassium present; and (c) integrated 1-D potentials of mean force for sodium or potassium movement that show less separation for the less selective E/D mutant than for WT. Overall, tight binding of a single favored ion to the selectivity filter, together with crucial inter-ion interactions within the pore, suggests that prokaryotic Nav channels use a selective strategy more akin to those of eukaryotic calcium and potassium channels than that of eukaryotic Nav channels.

Dataset Information

Molecular Dynamics of Ion Conduction through the Selectivity Filter of the NaVAb Sodium Channel.

Publications

Molecular Dynamics of Ion Conduction through the Selectivity Filter of the Na<sub>V</sub>Ab Sodium Channel.

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