Na+/Ca2+ selectivity in the bacterial voltage-gated sodium channel NavAb

The recent publication of a number of high resolution bacterial voltage-gated sodium channel structures has opened the door for the mechanisms employed by these channels to distinguish between ions to be elucidated. The way these channels select between Na+ and K+ has been investigated in computational studies, but the selectivity for Na+ over Ca2+ has not yet been studied in this way. Here we use molecular dynamics simulations to calculate the energetics of Na+ and Ca2+ transport through the channel. Single ion profiles show that Ca2+ experiences a large barrier midway through the selectivity filter that is not seen by Na+. This barrier is caused by the need for Ca2+ to partly dehydrate to pass through this region and the lack of compensating interactions with the protein. Multi-ion profiles show that ions can pass each other in the channel, which is why the presence of Ca2+ does not block Na+ conduction despite binding more strongly in the pore.

[1]  G. Torrie,et al.  Monte Carlo free energy estimates using non-Boltzmann sampling: Application to the sub-critical Lennard-Jones fluid , 1974 .

[2]  J. Ruppersberg.  Ion Channels in Excitable Membranes , 1996 .

[3]  Y. Mori,et al.  Molecular localization of regions in the L-type calcium channel critical for dihydropyridine action , 1993, Neuron.

[4]  A. L. Goldin,et al.  Resurgence of sodium channel research. , 2001, Annual review of physiology.

[5]  B. Wallace,et al.  Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing , 2012, Nature Communications.

[6]  S. Provencher.  A Fourier method for the analysis of exponential decay curves. , 1976, Biophysical journal.

[7]  L. Schild,et al.  Divalent cation selectivity for external block of voltage-dependent Na+ channels prolonged by batrachotoxin. Zn2+ induces discrete substates in cardiac Na+ channels , 1991, The Journal of general physiology.

[8]  B. Corry,et al.  The predominant role of coordination number in potassium channel selectivity. , 2007, Biophysical journal.

[9]  D. Busath,et al.  Calcium Block of Sodium Current in a Model Calcium Channel: Cylindrical Atomistic Pore with Glutamate Side Chains , 2004 .

[10]  T. Cheatham,et al.  Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations , 2008, The journal of physical chemistry. B.

[11]  A. Woodhull,et al.  Ionic Blockage of Sodium Channels in Nerve , 1973, The Journal of general physiology.

[12]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[13]  L Schild,et al.  On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel. , 1996, Biophysical journal.

[14]  William A. Catterall,et al.  Crystal structure of a voltage-gated sodium channel in two potentially inactivated states , 2012, Nature.

[15]  D. Clapham,et al.  A Prokaryotic Voltage-Gated Sodium Channel , 2001, Science.

[16]  R. Swendsen,et al.  THE weighted histogram analysis method for free‐energy calculations on biomolecules. I. The method , 1992 .

[17]  R. Tsien,et al.  Ca2+ channel selectivity at a single locus for high-affinity Ca2+ interactions , 1995, Neuron.

[18]  W. Wonderlin,et al.  Ion permeation, divalent ion block, and chemical modification of single sodium channels. Description by single- and double-occupancy rate- theory models [published erratum appears in J Gen Physiol 1994 May;103(5):937] , 1994, The Journal of general physiology.

[19]  Ben Corry,et al.  Mechanism of ion permeation and selectivity in a voltage gated sodium channel. , 2012, Journal of the American Chemical Society.

[20]  Jianhua He,et al.  Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel , 2012, Nature.

[21]  W. Catterall,et al.  From Ionic Currents to Molecular Mechanisms The Structure and Function of Voltage-Gated Sodium Channels , 2000, Neuron.

[22]  Daniel L. Minor,et al.  Voltage-gated sodium channel (NaV) protein dissection creates a set of functional pore-only proteins , 2011, Proceedings of the National Academy of Sciences.

[23]  W. Sather,et al.  The EEEE Locus Is the Sole High-affinity Ca 2 1 Binding Structure in the Pore of a Voltage-gated Ca 2 1 Channel Block by Ca 2 1 Entering from the Intracellular Pore Entrance , 2000 .

[24]  W. Almers,et al.  The Ca channel in skeletal muscle is a large pore. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. MacKinnon,et al.  Two identical noninteracting sites in an ion channel revealed by proton transfer. , 1994, Science.

[26]  W. Catterall,et al.  THE CRYSTAL STRUCTURE OF A VOLTAGE-GATED SODIUM CHANNEL , 2011, Nature.

[27]  Shin-Ho Chung,et al.  A model of sodium channels. , 2005, Biochimica et biophysica acta.

[28]  G. Phillips,et al.  Molecular mechanisms of calcium and magnesium binding to parvalbumin. , 2002, Biophysical journal.

[29]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[30]  K. Schulten,et al.  The allosteric role of the Ca2+ switch in adhesion and elasticity of C-cadherin. , 2008, Biophysical journal.

[31]  Shin-Ho Chung,et al.  Mechanisms of valence selectivity in biological ion channels , 2006, Cellular and Molecular Life Sciences CMLS.

[32]  D. Corey,et al.  Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction , 2012, Nature.

[33]  Denis Bucher,et al.  Polarization of water in the first hydration shell of K+ and Ca2+ ions. , 2008, The journal of physical chemistry. B.

[34]  T. Narahashi,et al.  Voltage-dependent calcium block of normal and tetramethrin-modified single sodium channels. , 1984, Biophysical journal.

[35]  Simone Furini,et al.  On Conduction in a Bacterial Sodium Channel , 2012, PLoS Comput. Biol..

[36]  Ben Corry,et al.  Intrinsic ion selectivity of narrow hydrophobic pores. , 2009, The journal of physical chemistry. B.

[37]  D. Gillespie.  Energetics of divalent selectivity in a calcium channel: the ryanodine receptor case study. , 2008, Biophysical journal.

[38]  D. Clapham,et al.  The Cation Selectivity Filter of the Bacterial Sodium Channel, NaChBac , 2002, The Journal of general physiology.

[39]  Alexander D. MacKerell,et al.  Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. , 2010, The journal of physical chemistry. B.

[40]  W. Sather,et al.  The Eeee Locus Is the Sole High-Affinity Ca2+ Binding Structure in the Pore of a Voltage-Gated Ca2+ Channel , 2000, The Journal of general physiology.

[41]  Jürg Hutter,et al.  Car–Parrinello molecular dynamics simulation of the hydrated calcium ion , 2002 .

[42]  B. Eisenberg,et al.  Binding and selectivity in L-type calcium channels: a mean spherical approximation. , 2000, Biophysical journal.

[43]  Shin-Ho Chung,et al.  Electrostatic basis of valence selectivity in cationic channels. , 2005, Biochimica et biophysica acta.

[44]  W. Stühmer,et al.  Calcium channel characteristics conferred on the sodium channel by single mutations , 1992, Nature.

[45]  S. Chung,et al.  Mechanisms of permeation and selectivity in calcium channels. , 2001, Biophysical journal.

[46]  B. Roux,et al.  Molecular dynamics study of calbindin D9k in the apo and singly and doubly calcium‐loaded states , 1998, Proteins.

[47]  R. Tsien,et al.  Mechanism of ion permeation through calcium channels , 1984, Nature.

[48]  S. Kuyucak,et al.  A model of calcium channels. , 2000, Biochimica et biophysica acta.

[49]  Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion , 2009, The Journal of general physiology.

[50]  Edward Moczydlowski,et al.  On the Structural Basis for Size-selective Permeation of Organic Cations through the Voltage-gated Sodium Channel , 1997, The Journal of general physiology.