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Sodium binding sites and permeation mechanism in the NaChBac channel : a molecular dynamics study
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Guardiani, Carlo, Rodger, P. Mark, Fedorenko, Olena A., Roberts, Stephen K. and Khovanov, Igor A. (2016) Sodium binding sites and permeation mechanism in the NaChBac channel : a molecular dynamics study. Journal of Chemical Theory and Computation, 13 (3). pp. 1389-1400. doi:10.1021/acs.jctc.6b01035
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Official URL: http://dx.doi.org/10.1021/acs.jctc.6b01035
Abstract
NaChBac was the first discovered bacterial sodium voltage-dependent channel, yet computational studies are still limited due to the lack of a crystal structure. In this work, a pore-only construct built using the NavMs template was investigated using unbiased molecular dynamics and metadynamics. The potential of mean force (PMF) from the unbiased run features four minima, three of which correspond to sites IN, CEN, and HFS discovered in NavAb. During the run, the selectivity filter (SF) is spontaneously occupied by two ions, and frequent access of a third one is often observed. In the innermost sites IN and CEN, Na+ is fully hydrated by six water molecules and occupies an on-axis position. In site HFS sodium interacts with a glutamate and a serine from the same subunit and is forced to adopt an off-axis placement. Metadynamics simulations biasing one and two ions show an energy barrier in the SF that prevents single-ion permeation. An analysis of the permeation mechanism was performed both computing minimum energy paths in the axial–axial PMF and through a combination of Markov state modeling and transition path theory. Both approaches reveal a knock-on mechanism involving at least two but possibly three ions. The currents predicted from the unbiased simulation using linear response theory are in excellent agreement with single-channel patch-clamp recordings.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | Q Science > QP Physiology | ||||||||||||
| Divisions: | Faculty of Science > Chemistry Faculty of Science > Engineering Faculty of Science > Life Sciences (2010- ) Faculty of Science > Centre for Scientific Computing |
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| Library of Congress Subject Headings (LCSH): | Sodium channels , Potassium channels, Cations, Molecular Dynamics | ||||||||||||
| Journal or Publication Title: | Journal of Chemical Theory and Computation | ||||||||||||
| Publisher: | American Chemical Society | ||||||||||||
| ISSN: | 1549-9618 | ||||||||||||
| Official Date: | 26 December 2016 | ||||||||||||
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| Date of first compliant deposit: | 15 February 2017 | ||||||||||||
| Volume: | 13 | ||||||||||||
| Number: | 3 | ||||||||||||
| Page Range: | pp. 1389-1400 | ||||||||||||
| DOI: | 10.1021/acs.jctc.6b01035 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
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