Catalysis of Na+ permeation in the bacterial sodium channel NavAb.

Catalysis of Na+ permeation in the bacterial sodium channel NavAb. Chakrabarti, N., Ing, C., Payandeh, J., Zheng, N., Catterall, W., a., & Pomès, R. Proceedings of the National Academy of Sciences of the United States of America, 6, 2013.

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Catalysis of Na+ permeation in the bacterial sodium channel NavAb. [link]

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Determination of a high-resolution 3D structure of voltage-gated sodium channel NaVAb opens the way to elucidating the mechanism of ion conductance and selectivity. To examine permeation of Na(+) through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of NaVAb in an explicit, hydrated lipid bilayer at 0 mV in 150 mM NaCl, for a total simulation time of 21.6 μs. Although the cytoplasmic end of the pore is closed, reversible influx and efflux of Na(+) through the selectivity filter occurred spontaneously during simulations, leading to equilibrium movement of Na(+) between the extracellular medium and the central cavity of the channel. Analysis of Na(+) dynamics reveals a knock-on mechanism of ion permeation characterized by alternating occupancy of the channel by 2 and 3 Na(+) ions, with a computed rate of translocation of (6 ± 1) × 10(6) ions⋅s(-1) that is consistent with expectations from electrophysiological studies. The binding of Na(+) is intimately coupled to conformational isomerization of the four E177 side chains lining the extracellular end of the selectivity filter. The reciprocal coordination of variable numbers of Na(+) ions and carboxylate groups leads to their condensation into ionic clusters of variable charge and spatial arrangement. Structural fluctuations of these ionic clusters result in a myriad of ion binding modes and foster a highly degenerate, liquid-like energy landscape propitious to Na(+) diffusion. By stabilizing multiple ionic occupancy states while helping Na(+) ions diffuse within the selectivity filter, the conformational flexibility of E177 side chains underpins the knock-on mechanism of Na(+) permeation.

@article{
 title = {Catalysis of Na+ permeation in the bacterial sodium channel NavAb.},
 type = {article},
 year = {2013},
 volume = {110},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23803856},
 month = {6},
 day = {26},
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 abstract = {Determination of a high-resolution 3D structure of voltage-gated sodium channel NaVAb opens the way to elucidating the mechanism of ion conductance and selectivity. To examine permeation of Na(+) through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of NaVAb in an explicit, hydrated lipid bilayer at 0 mV in 150 mM NaCl, for a total simulation time of 21.6 μs. Although the cytoplasmic end of the pore is closed, reversible influx and efflux of Na(+) through the selectivity filter occurred spontaneously during simulations, leading to equilibrium movement of Na(+) between the extracellular medium and the central cavity of the channel. Analysis of Na(+) dynamics reveals a knock-on mechanism of ion permeation characterized by alternating occupancy of the channel by 2 and 3 Na(+) ions, with a computed rate of translocation of (6 ± 1) × 10(6) ions⋅s(-1) that is consistent with expectations from electrophysiological studies. The binding of Na(+) is intimately coupled to conformational isomerization of the four E177 side chains lining the extracellular end of the selectivity filter. The reciprocal coordination of variable numbers of Na(+) ions and carboxylate groups leads to their condensation into ionic clusters of variable charge and spatial arrangement. Structural fluctuations of these ionic clusters result in a myriad of ion binding modes and foster a highly degenerate, liquid-like energy landscape propitious to Na(+) diffusion. By stabilizing multiple ionic occupancy states while helping Na(+) ions diffuse within the selectivity filter, the conformational flexibility of E177 side chains underpins the knock-on mechanism of Na(+) permeation.},
 bibtype = {article},
 author = {Chakrabarti, Nilmadhab and Ing, Christopher and Payandeh, Jian and Zheng, Ning and Catterall, William a and Pomès, Régis},
 doi = {10.1073/pnas.1309452110},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {28}
}

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