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Title: Bases of Bacterial Sodium Channel Selectivity Among Organic Cations

Abstract

Hille’s (1971) seminal study of organic cation selectivity of eukaryotic voltage-gated sodium channels showed a sharp size cut-off for ion permeation, such that no ion possessing a methyl group was permeant. Using the prokaryotic channel, NaChBac, we found some similarity and two peculiar differences in the selectivity profiles for small polyatomic cations. First, we identified a diverse group of minimally permeant cations for wildtype NaChBac, ranging in sizes from ammonium to guanidinium and tetramethylammonium; and second, for both ammonium and hydrazinium, the charge-conserving selectivity filter mutation (E191D) yielded substantial increases in relative permeability (P X/P Na). The relative permeabilities varied inversely with relative Kd calculated from 1D Potential of Mean Force profiles (PMFs) for the single cations traversing the channel. Several of the cations bound more strongly than Na +, and hence appear to act as blockers, as well as charge carriers. Consistent with experimental observations, the E191D mutation had little impact on Na+ binding to the selectivity filter, but disrupted the binding of ammonium and hydrazinium, consequently facilitating ion permeation across the NaChBac-like filter. We concluded that for prokaryotic sodium channels, a fine balance among filter size, binding affinity, occupancy, and flexibility seems to contribute to observed functional differences.

Authors:
 [1]; ORCiD logo [2];  [3]; ORCiD logo [4]; ORCiD logo [4]
  1. Chinese Academy of Sciences (CAS), Changchun (China); Univ. of Calgary, AB (Canada)
  2. Univ. of Calgary, AB (Canada); Univ. of Wollongong, NSW (Australia)
  3. Univ. of Calgary, AB (Canada); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  4. Univ. of Calgary, AB (Canada)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1574758
Report Number(s):
LA-UR-19-29893
Journal ID: ISSN 2045-2322
Grant/Contract Number:  
89233218CNA000001
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Sodium Ion Channels

Citation Formats

Wang, Yibo, Finol-Urdaneta, Rocio K., Ngo, Van Anh, French, Robert J., and Noskov, Sergei Yu. Bases of Bacterial Sodium Channel Selectivity Among Organic Cations. United States: N. p., 2019. Web. doi:10.1038/s41598-019-51605-y.
Wang, Yibo, Finol-Urdaneta, Rocio K., Ngo, Van Anh, French, Robert J., & Noskov, Sergei Yu. Bases of Bacterial Sodium Channel Selectivity Among Organic Cations. United States. doi:10.1038/s41598-019-51605-y.
Wang, Yibo, Finol-Urdaneta, Rocio K., Ngo, Van Anh, French, Robert J., and Noskov, Sergei Yu. Thu . "Bases of Bacterial Sodium Channel Selectivity Among Organic Cations". United States. doi:10.1038/s41598-019-51605-y. https://www.osti.gov/servlets/purl/1574758.
@article{osti_1574758,
title = {Bases of Bacterial Sodium Channel Selectivity Among Organic Cations},
author = {Wang, Yibo and Finol-Urdaneta, Rocio K. and Ngo, Van Anh and French, Robert J. and Noskov, Sergei Yu.},
abstractNote = {Hille’s (1971) seminal study of organic cation selectivity of eukaryotic voltage-gated sodium channels showed a sharp size cut-off for ion permeation, such that no ion possessing a methyl group was permeant. Using the prokaryotic channel, NaChBac, we found some similarity and two peculiar differences in the selectivity profiles for small polyatomic cations. First, we identified a diverse group of minimally permeant cations for wildtype NaChBac, ranging in sizes from ammonium to guanidinium and tetramethylammonium; and second, for both ammonium and hydrazinium, the charge-conserving selectivity filter mutation (E191D) yielded substantial increases in relative permeability (PX/PNa). The relative permeabilities varied inversely with relative Kd calculated from 1D Potential of Mean Force profiles (PMFs) for the single cations traversing the channel. Several of the cations bound more strongly than Na+, and hence appear to act as blockers, as well as charge carriers. Consistent with experimental observations, the E191D mutation had little impact on Na+ binding to the selectivity filter, but disrupted the binding of ammonium and hydrazinium, consequently facilitating ion permeation across the NaChBac-like filter. We concluded that for prokaryotic sodium channels, a fine balance among filter size, binding affinity, occupancy, and flexibility seems to contribute to observed functional differences.},
doi = {10.1038/s41598-019-51605-y},
journal = {Scientific Reports},
number = 1,
volume = 9,
place = {United States},
year = {2019},
month = {10}
}

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Works referenced in this record:

The Permeability of the Sodium Channel to Organic Cations in Myelinated Nerve
journal, December 1971


The Permeability of the Sodium Channel to Metal Cations in Myelinated Nerve
journal, June 1972


Molecular basis of ion permeability in a voltage‐gated sodium channel
journal, February 2016

  • Naylor, Claire E.; Bagnéris, Claire; DeCaen, Paul G.
  • The EMBO Journal, Vol. 35, Issue 8
  • DOI: 10.15252/embj.201593285

Crystal structure of a voltage-gated sodium channel in two potentially inactivated states
journal, May 2012

  • Payandeh, Jian; Gamal El-Din, Tamer M.; Scheuer, Todd
  • Nature, Vol. 486, Issue 7401
  • DOI: 10.1038/nature11077

Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel
journal, May 2012


The crystal structure of a voltage-gated sodium channel
journal, July 2011

  • Payandeh, Jian; Scheuer, Todd; Zheng, Ning
  • Nature, Vol. 475, Issue 7356
  • DOI: 10.1038/nature10238

Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution
journal, February 2017


Effects of the Protonation State of the EEEE Motif of a Bacterial Na+-channel on Conduction and Pore Structure
journal, May 2014


Mechanism of Ion Permeation and Selectivity in a Voltage Gated Sodium Channel
journal, January 2012

  • Corry, Ben; Thomas, Michael
  • Journal of the American Chemical Society, Vol. 134, Issue 3
  • DOI: 10.1021/Ja210020h

Analysis of the selectivity filter of the voltage-gated sodium channel NavRh
journal, December 2012


The Cation Selectivity Filter of the Bacterial Sodium Channel, NaChBac
journal, November 2002

  • Yue, Lixia; Navarro, Betsy; Ren, Dejian
  • The Journal of General Physiology, Vol. 120, Issue 6
  • DOI: 10.1085/Jgp.20028699

K+ Block Is the Mechanism of Functional Asymmetry in Bacterial Nav Channels
journal, January 2016


Selective ion permeation involves complexation with carboxylates and lysine in a model human sodium channel
journal, September 2018


Molecular Dynamics of Ion Conduction through the Selectivity Filter of the Na V Ab Sodium Channel
journal, October 2018

  • Callahan, Karen M.; Roux, Benoît
  • The Journal of Physical Chemistry B, Vol. 122, Issue 44
  • DOI: 10.1021/acs.jpcb.8b09678

Role of Channel Fluctuations in Ion Transport and Selectivity in Bacterial Sodium Channel NavAb
journal, February 2017

  • Ing, Christopher; Chakrabarti, Nilmadhab; Zheng, Ning
  • Biophysical Journal, Vol. 112, Issue 3
  • DOI: 10.1016/j.bpj.2016.11.598

Catalysis of Na+ permeation in the bacterial sodium channel NaVAb
journal, June 2013

  • Chakrabarti, N.; Ing, C.; Payandeh, J.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 28
  • DOI: 10.1073/pnas.1309452110

Different Inward and Outward Conduction Mechanisms in NaVMs Suggested by Molecular Dynamics Simulations
journal, July 2014


Ion-triggered selectivity in bacterial sodium channels
journal, May 2018

  • Furini, Simone; Domene, Carmen
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 21
  • DOI: 10.1073/pnas.1722516115

Revisiting Voltage-Dependent Relief of Block in Ion Channels: A Mechanism Independent of Punchthrough
journal, June 2004


Selective Open-Channel Block of Shaker (Kv1) Potassium Channels by S-Nitrosodithiothreitol (Sndtt)
journal, June 2001

  • Brock, Mathew W.; Mathes, Chris; Gilly, William F.
  • The Journal of General Physiology, Vol. 118, Issue 1
  • DOI: 10.1085/jgp.118.1.113

Internal block of human heart sodium channels by symmetrical tetra- alkylammoniums
journal, September 1994


The effect of tetramethylammonium on single sodium channel currents
journal, November 1981


Modeling P-Loops Domain of Sodium Channel: Homology with Potassium Channels and Interaction with Ligands
journal, January 2005


Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy
journal, January 2014

  • Finol-Urdaneta, Rocio K.; Wang, Yibo; Al-Sabi, Ahmed
  • The Journal of General Physiology, Vol. 143, Issue 2
  • DOI: 10.1085/jgp.201311037

On Conduction in a Bacterial Sodium Channel
journal, April 2012


Conduction in a Biological Sodium Selective Channel
journal, March 2013

  • Stock, Letícia; Delemotte, Lucie; Carnevale, Vincenzo
  • The Journal of Physical Chemistry B, Vol. 117, Issue 14
  • DOI: 10.1021/jp401403b

Molecular dynamics of ion transport through the open conformation of a bacterial voltage-gated sodium channel
journal, March 2013

  • Ulmschneider, M. B.; Bagneris, C.; McCusker, E. C.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 16
  • DOI: 10.1073/pnas.1214667110

Sodium Ion Binding Sites and Hydration in the Lumen of a Bacterial Ion Channel from Molecular Dynamics Simulations
journal, September 2011

  • Carnevale, Vincenzo; Treptow, Werner; Klein, Michael L.
  • The Journal of Physical Chemistry Letters, Vol. 2, Issue 19
  • DOI: 10.1021/jz2011379

Ion solvation and structural stability in a sodium channel investigated by molecular dynamics calculations
journal, November 2012

  • Qiu, Hu; Shen, Rong; Guo, Wanlin
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1818, Issue 11
  • DOI: 10.1016/j.bbamem.2012.06.003

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel
journal, February 2014

  • Boiteux, Céline; Vorobyov, Igor; Allen, Toby W.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 9
  • DOI: 10.1073/pnas.1320907111

Junction potentials, electrode standard potentials, and other problems in interpreting electrical properties of membranes
journal, December 1970

  • Barry, Peter H.; Diamond, Jared M.
  • The Journal of Membrane Biology, Vol. 3, Issue 1
  • DOI: 10.1007/BF01868010

Two mechanisms of ion selectivity in protein binding sites
journal, November 2010

  • Yu, H.; Noskov, S. Y.; Roux, B.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 47
  • DOI: 10.1073/pnas.1007150107

Molecular Mechanism of Conductance Enhancement in Narrow Cation-Selective Membrane Channels
journal, June 2018

  • Miranda, Williams E.; Ngo, Van A.; Wang, Ruiwu
  • The Journal of Physical Chemistry Letters, Vol. 9, Issue 12
  • DOI: 10.1021/acs.jpclett.8b01005

Redesigning allosteric activation in an enzyme
journal, February 2011

  • Rana, S.; Pozzi, N.; Pelc, L. A.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 13
  • DOI: 10.1073/pnas.1018860108

Molecular Mechanisms of K+ Selectivity in Na/K Pump
journal, January 2012

  • Yu, Haibo; Ratheal, Ian; Artigas, Pablo
  • Australian Journal of Chemistry, Vol. 65, Issue 5
  • DOI: 10.1071/CH12026

Mechanism of the Association between Na + Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters
journal, April 2015

  • Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng
  • Journal of Biological Chemistry, Vol. 290, Issue 22
  • DOI: 10.1074/jbc.M114.625343

Batrachotoxin acts as a stent to hold open homotetrameric prokaryotic voltage-gated sodium channels
journal, December 2018

  • Finol-Urdaneta, Rocio K.; McArthur, Jeffrey R.; Goldschen-Ohm, Marcel P.
  • The Journal of General Physiology, Vol. 151, Issue 2
  • DOI: 10.1085/jgp.201812278

CHARMM-GUI: A web-based graphical user interface for CHARMM
journal, March 2008

  • Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G.
  • Journal of Computational Chemistry, Vol. 29, Issue 11
  • DOI: 10.1002/jcc.20945

CHARMM: The biomolecular simulation program
journal, July 2009

  • Brooks, B. R.; Brooks, C. L.; Mackerell, A. D.
  • Journal of Computational Chemistry, Vol. 30, Issue 10
  • DOI: 10.1002/jcc.21287

All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins
journal, April 1998

  • MacKerell, A. D.; Bashford, D.; Bellott, M.
  • The Journal of Physical Chemistry B, Vol. 102, Issue 18
  • DOI: 10.1021/jp973084f

Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands
journal, October 2004

  • Noskov, Sergei Yu.; Bernèche, Simon; Roux, Benoît
  • Nature, Vol. 431, Issue 7010
  • DOI: 10.1038/nature02943

Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ 1 and χ 2 Dihedral Angles
journal, August 2012

  • Best, Robert B.; Zhu, Xiao; Shim, Jihyun
  • Journal of Chemical Theory and Computation, Vol. 8, Issue 9
  • DOI: 10.1021/ct300400x

A smooth particle mesh Ewald method
journal, November 1995

  • Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.
  • The Journal of Chemical Physics, Vol. 103, Issue 19
  • DOI: 10.1063/1.470117

Molecular Strategies to Achieve Selective Conductance in NaK Channel Variants
journal, February 2014

  • Wang, Yibo; Chamberlin, Adam C.; Noskov, Sergei Yu.
  • The Journal of Physical Chemistry B, Vol. 118, Issue 8
  • DOI: 10.1021/jp4107537

Automated Force Field Parameterization for Nonpolarizable and Polarizable Atomic Models Based on Ab Initio Target Data
journal, July 2013

  • Huang, Lei; Roux, Benoît
  • Journal of Chemical Theory and Computation, Vol. 9, Issue 8
  • DOI: 10.1021/ct4003477

CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
journal, January 2009

  • Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.
  • Journal of Computational Chemistry
  • DOI: 10.1002/jcc.21367

Inclusion of Many-Body Effects in the Additive CHARMM Protein CMAP Potential Results in Enhanced Cooperativity of α-Helix and β-Hairpin Formation
journal, September 2012


Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing
journal, November 2012

  • Vanommeslaeghe, K.; MacKerell, A. D.
  • Journal of Chemical Information and Modeling, Vol. 52, Issue 12
  • DOI: 10.1021/ci300363c

Automation of the CHARMM General Force Field (CGenFF) II: Assignment of Bonded Parameters and Partial Atomic Charges
journal, November 2012

  • Vanommeslaeghe, K.; Raman, E. Prabhu; MacKerell, A. D.
  • Journal of Chemical Information and Modeling, Vol. 52, Issue 12
  • DOI: 10.1021/ci3003649

Comment on “Free energy simulations of single and double ion occupancy in gramicidin A” [J. Chem. Phys. 126, 105103 (2007)]
journal, June 2008

  • Roux, Benoît; Andersen, Olaf S.; Allen, Toby W.
  • The Journal of Chemical Physics, Vol. 128, Issue 22
  • DOI: 10.1063/1.2931568

Energetics of ion conduction through the gramicidin channel
journal, December 2003

  • Allen, T. W.; Andersen, O. S.; Roux, B.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 1
  • DOI: 10.1073/pnas.2635314100

Computation of Absolute Hydration and Binding Free Energy with Free Energy Perturbation Distributed Replica-Exchange Molecular Dynamics
journal, August 2009

  • Jiang, Wei; Hodoscek, Milan; Roux, Benoît
  • Journal of Chemical Theory and Computation, Vol. 5, Issue 10
  • DOI: 10.1021/ct900223z

Calculation of Free Energy Landscape in Multi-Dimensions with Hamiltonian-Exchange Umbrella Sampling on Petascale Supercomputer
journal, October 2012

  • Jiang, Wei; Luo, Yun; Maragliano, Luca
  • Journal of Chemical Theory and Computation, Vol. 8, Issue 11
  • DOI: 10.1021/ct300468g

On the Hamiltonian replica exchange method for efficient sampling of biomolecular systems: Application to protein structure prediction
journal, May 2002

  • Fukunishi, Hiroaki; Watanabe, Osamu; Takada, Shoji
  • The Journal of Chemical Physics, Vol. 116, Issue 20
  • DOI: 10.1063/1.1472510

On the selective ion binding hypothesis for potassium channels
journal, October 2011

  • Kim, I.; Allen, T. W.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 44
  • DOI: 10.1073/pnas.1110735108

THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method
journal, October 1992

  • Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal
  • Journal of Computational Chemistry, Vol. 13, Issue 8
  • DOI: 10.1002/jcc.540130812

The calculation of the potential of mean force using computer simulations
journal, September 1995