Advertisement

The sliding-helix voltage sensor: mesoscale views of a robust structure–function relationship

Abstract

The voltage sensor (VS) domain of voltage-gated ion channels underlies the electrical excitability of living cells. We simulate a mesoscale model of the VS domain to determine the functional consequences of some of its physical elements. Our mesoscale model is based on VS charges, linear dielectrics, and whole-body motion, applied to an S4 “sliding helix.” The electrostatics under voltage-clamped boundary conditions are solved consistently using a boundary-element method. Based on electrostatic configurational energy, statistical-mechanical expectations of the experimentally observable relation between displaced charge and membrane voltage are predicted. Consequences of the model are investigated for variations of S4 configuration (α- and 310-helical), countercharge alignment with S4 charges, protein polarizability, geometry of the gating canal, screening of S4 charges by the baths, and fixed charges located at the bath interfaces. The sliding-helix VS domain has an inherent electrostatic stability in the explored parameter space: countercharges present in the region of weak dielectric always retain an equivalent S4 charge in that region but allow sliding movements displacing 3–4 e 0. That movement is sensitive to small energy variations (<2 kT) along the path dependent on a number of electrostatic parameters tested in our simulations. These simulations show how the slope of the relation between displaced charge and voltage could be tuned in a channel.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Bjelkmar P, Niemelä PS, Vattulainen I, Lindahl E (2009) Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel. PLoS Comput Biol 5(2):e1000289 doi:10.1371/journal.pcbi.1000289

  2. Boda D, Valiskó M, Eisenberg B, Nonner W, Henderson D, Gillespie D (2006) The effect of protein dielectric coefficient on the ionic selectivity of a calcium channel. J Chem Phys 125(3):34901 doi:10.1063/1.2212423

  3. Campos FV, Chanda B, Roux B, Bezanilla F (2007) Two atomic constraints unambiguously position the S4 segment relative to S1 and S2 segments in the closed state of Shaker K channel. Proc Natl Acad Sci U S A 104(19):7904–7909 doi:10.1073/pnas.0702638104

  4. Cubitt TS, Eisert J, Wolf MM (2012) Extracting dynamical equations from experimental data is NP hard. Phys Rev Lett 108:120503 doi:10.1103/PhysRevLett.108.120503

  5. Dani JA, Sanchez JA, Hille B (1983) Lyotropic anions. Na channel gating and Ca electrode response. J Gen Physiol 81:255–281 doi:10.1085/jgp.81.2.255

  6. Delemotte L, Treptow W, Klein ML, Tarek M (2010) Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2. Biophys J 99(9):L72–L74 doi:10.1016/j.bpj.2010.08.069

  7. Doi M (2011) Onsager’s variational principle in soft matter. J Phys Condens Matter 23(28):284118. http://stacks.iop.org/0953-8984/23/i=28/a=284118

  8. Elinder F, Liu Y, Århem P (1998) Divalent cation effects on the Shaker K channel suggest a pentapeptide sequence as determinant of functional surface charge density. J Membr Biol 165(2):183–189 doi:10.1007/s002329900432

  9. Elinder F, Männikkö R, Larsson HP (2001) S4 charges move close to residues in the pore domain during activation in a K channel. J Gen Physiol 118(1):1–10 doi:0.1085/jgp.118.1.1-a

  10. Elinder F, Århem P (1999) Role of individual surface charges of voltage-gated K channels. Biophys J 77(3):1358–1362 doi:10.1016/S0006-3495(99)76984-5

  11. Frankenhaeuser B, Hodgkin AL (1957) The action of calcium on the electrical properties of squid axons. J Physiol 137(2):218–244. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1362975

  12. Gandhi CS, Isacoff EY (2002) Molecular models of voltage sensing. J Gen Physiol 120:455–463 doi:10.1085/jgp.20028678

  13. Grabe M, Lecar H, Jan YN, Jan LY (2004) A quantitative assessment of models for voltage-dependent gating of ion channels. Proc Natl Acad Sci U S A 101(51):17640–17645 doi:10.1073/pnas.0408116101

  14. He Z (2001) Review of the Shockley-Ramo theorem and its application in semiconductor gamma-ray detectors. Nucl Instr Meth A 463(1–2):250–267 doi:10.1016/S0168-9002(01)00223-6

  15. Hille B (2001) Ion channels of excitable membranes, 3rd edn. Sinauer Associates, Sunderland

  16. Hodgkin A, Huxley A (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117(4):500–544. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1392413

  17. Islas LD, Sigworth FJ (2001) Electrostatics and the gating pore of Shaker potassium channels. J Gen Physiol 117(1):69–90 doi:10.1085/jgp.117.1.69

  18. Jensen MO, Jogini V, Borhani DW, Leffler AE, Dror RO, Shaw DE (2012) Mechanism of voltage gating in potassium channels. Science 336:229–233 doi:10.1126/science.1216533

  19. Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R (2003) X-ray structure of a voltage-dependent K+ channel. Nature 423(6935):33–41 doi:10.1038/nature01580

  20. Khalili-Araghi F, Jogini V, Yarov-Yarovoy V, Tajkhorshid E, Roux B, Schulten K (2010) Calculation of the gating charge for the Kv1.2 voltage-activated potassium channel. Biophys J 98(10):2189–2198 doi:10.1016/j.bpj.2010.02.056

  21. Khalili-Araghi F, Tajkhorshid E, Roux B, Schulten K (2012) Molecular dynamics investigation of the ω-current in the Kv1.2 voltage sensor domains. Biophys J 102(2):258–267 doi:10.1016/j.bpj.2011.10.057

  22. Larsson HP, Elinder F (2000) A conserved glutamate is important for slow inactivation in K+ channels. Neuron 27(3):573–583 doi:10.1016/S0896-6273(00)00067-2

  23. Lecar H, Larsson HP, Grabe M (2003) Electrostatic model of S4 motion in voltage-gated ion channels. Biophys J 85(5):2854–2864 doi:10.1016/S0006-3495(03)74708-0

  24. Long SB, Campbell EB, MacKinnon R (2005a) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309(5736):897–903 doi:10.1126/science.1116269

  25. Long SB, Campbell EB, MacKinnon R (2005b) Voltage sensor of Kv1.2: Structural basis of electromechanical coupling. Science 309(5736):903–908 doi:10.1126/science.1116270

  26. Long SB, Tao X, Campbell EB, MacKinnon R (2007) Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450(7168):376–382 doi:10.1038/nature06265

  27. Neumcke B, Nonner W, Stämpfli R (1978) Gating currents in excitable membranes. Int Rev Biochem Biochem Cell Walls Membr II 19:129–155

  28. Nishizawa M, Nishizawa K (2008) Molecular dynamics simulation of Kv channel voltage sensor helix in a lipid membrane with applied electric field. Biophys J 95(4):1729–1744 doi:10.1529/biophysj.108.130658

  29. Papazian DM, Shao XM, Seoh SA, Mock AF, Huang Y, Wainstock DH (1995) Electrostatic interactions of S4 voltage sensor in Shaker K+ channel. Neuron 14(6):1293–1301 doi:10.1016/0896-6273(95)90276-7

  30. Pathak MM, Yarov-Yarovoy V, Agarwal G, Roux B, Barth P, Kohout S, Tombola F, Isacoff EY (2007) Closing in on the resting state of the Shaker K+ channel. Neuron 56(1):124–140 doi:10.1016/j.neuron.2007.09.023

  31. Payandeh J, Scheuer T, Zheng N, Catterall WA (2011) The crystal structure of a voltage-gated sodium channel. Nature 475(7356):353–358 doi:10.1038/nature10238

  32. Peyser A, Nonner W (2012) Voltage sensing in ion channels: Mesoscale simulations of biological devices. Phys Rev E Stat Nonlin Soft Matter Phys 86:011910 doi:10.1103/PhysRevE.86.011910

  33. Schmidt D, Jiang QX, MacKinnon R (2006) Phospholipids and the origin of cationic gating charges in voltage sensors. Nature 444(7120):775–779 doi:10.1038/nature05416

  34. Schow EV, Freites JA, Gogna K, White SH, Tobias DJ (2010) Down-state model of the voltage-sensing domain of a potassium channel. Biophys J 98(12):2857–2866 doi:10.1016/j.bpj.2010.03.031

  35. Schutz CN, Warshel A (2001) What are the dielectric "constants" of proteins and how to validate electrostatic models? Proteins 44(4):400–417 doi:10.1002/prot.1106

  36. Schwaiger CS, Bjelkmar P, Hess B, Lindahl E (2011) 310-helix conformation facilitates the transition of a voltage sensor S4 segment toward the down state. Biophys J 100(6):1446–1454 doi:10.1016/j.bpj.2011.02.003

  37. Seoh SA, Sigg D, Papazian DM, Bezanilla F (1996) Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron 16(6):1159–1167 doi:10.1016/S0896-6273(00)80142-7

  38. Tao X, Lee A, Limapichat W, Dougherty DA, MacKinnon R (2010) A gating charge transfer center in voltage sensors. Science 328(5974):67–73 doi:10.1126/science.1185954

  39. Yarov-Yarovoy V, Baker D, Catterall WA (2006) Voltage sensor conformations in the open and closed states in ROSETTA structural models of K+ channels. Proc Natl Acad Sci USA 103(19):7292–7297 doi:10.1073/pnas.0602350103

Download references

Acknowledgments

The authors are grateful for the support of the National Institutes of Health (grant GM083161) to W.N. and a Graduate Research Fellowship of the National Science Foundation to A.P. We thank Drs. Alice Holohean, Peter Larsson, and Karl Magleby for helpful discussions.

Author information

Correspondence to Alexander Peyser.

Electronic supplementary material

Below is the link to the electronic supplementary material.

MPG (19,598 KB)

MPG (19,598 KB)

MPG (19,596 KB)

MPG (19,598 KB)

PDF (3,260 KB)

EPS (224 KB)

TIFF (903 KB)

TIFF (878 KB)

TIFF (924 KB)

TIFF (864 KB)

EPS (85 KB)

MPG (19,598 KB)

MPG (19,598 KB)

MPG (19,596 KB)

MPG (19,598 KB)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Peyser, A., Nonner, W. The sliding-helix voltage sensor: mesoscale views of a robust structure–function relationship. Eur Biophys J 41, 705–721 (2012) doi:10.1007/s00249-012-0847-z

Download citation

Keywords

  • Ion channels
  • Computer simulation
  • Potassium channels
  • Voltage gated
  • Voltage sensor domain