Studying Kv Channels Function using Computational Methods

  • Audrey Deyawe
  • Marina A. Kasimova
  • Lucie Delemotte
  • Gildas Loussouarn
  • Mounir TarekEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1684)


In recent years, molecular modeling techniques, combined with MD simulations, provided significant insights on voltage-gated (Kv) potassium channels intrinsic properties. Among the success stories are the highlight of molecular level details of the effects of mutations, the unraveling of several metastable intermediate states, and the influence of a particular lipid, PIP2, in the stability and the modulation of Kv channel function. These computational studies offered a detailed view that could not have been reached through experimental studies alone. With the increase of cross disciplinary studies, numerous experiments provided validation of these computational results, which endows an increase in the reliability of molecular modeling for the study of Kv channels. This chapter offers a description of the main techniques used to model Kv channels at the atomistic level.

Key words

Voltage-gated ion channels Homology modeling Molecular dynamics simulations Transmembrane potential Gating charge Lipid membranes 



Results of the MD simulations were obtained thanks to generous allocation of computer time from GENCI France.


  1. 1.
    Hille B (2001) Ion channels of excitable membranes, 3rd edn. Sinauer, Sunderland, MAGoogle Scholar
  2. 2.
    Jouni M, Si-Tayeb K, Es-Salah-Lamoureux Z, Latypova X, Champon B, Caillaud A, Rungoat A, Charpentier F, Loussouarn G, Baró I, Zibara K, Lemarchand P, Gaborit N (2015) Toward personalized medicine: using cardiomyocytes differentiated from urine-derived pluripotent stem cells to recapitulate electrophysiological characteristics of Type 2 long QT syndrome. J Am Heart Assoc 4:e002159. doi: 10.1161/JAHA.115.002159 PubMedPubMedCentralGoogle Scholar
  3. 3.
    Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RFJ, Faivre L, Barc J, Dina C, Bertaux G, Barthez O, Thauvin-Robinet C, Charron P, Fressart V, Maltret A, Villain E, Baron E, Mérot J, Turpault R, Coudière Y, Charpentier F, Schott J-J, Loussouarn G, Wilde AAM, Wolf J-E, Baró I, Kyndt F, Probst V (2012) Multifocal ectopic purkinje-related premature contractions. J Am Coll Cardiol 60:144–156. doi: 10.1016/j.jacc.2012.02.052 PubMedCrossRefGoogle Scholar
  4. 4.
    Loussouarn G, Sternberg D, Nicole S, Marionneau C, Le Bouffant F, Toumaniantz G, Barc J, Malak OA, Fressart V, Péréon Y, Baró I, Charpentier F (2016) Physiological and pathophysiological insights of Nav1.4 and Nav1.5 comparison. Front Pharmacol 6:314. doi: 10.3389/fphar.2015.00314 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Park K-H, Piron J, Dahimene S, Mérot J, Baró I, Escande D, Loussouarn G (2005) Impaired KCNQ1-KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome. Circ Res 96:730–739. doi: 10.1161/01.RES.0000161451.04649.a8 PubMedCrossRefGoogle Scholar
  6. 6.
    Yang Y, Vasylyev DV, Dib-Hajj F, Veeramah KR, Hammer MF, Dib-Hajj SD, Waxman SG (2013) Multistate structural modeling and voltage-clamp analysis of epilepsy/autism mutation Kv10.2-R327H demonstrate the role of this residue in stabilizing the channel closed state. J Neurosci 33:16586–16593. doi: 10.1523/JNEUROSCI.2307-13.2013 PubMedCrossRefGoogle Scholar
  7. 7.
    Nattel S, Maguy A, Le Bouter S, Yeh Y-H (2007) Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 87:425–456. doi: 10.1152/physrev.00014.2006 PubMedCrossRefGoogle Scholar
  8. 8.
    Charpentier F, Mérot J, Loussouarn G, Baró I (2010) Delayed rectifier K+ currents and cardiac repolarization. J Mol Cell Cardiol 48:37–44. doi: 10.1016/j.yjmcc.2009.08.005 PubMedCrossRefGoogle Scholar
  9. 9.
    Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ (2000) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403:196–199. doi: 10.1038/35003200 PubMedCrossRefGoogle Scholar
  10. 10.
    Vallon V, Grahammer F, Volkl H, Sandu CD, Richter K, Rexhepaj R, Gerlach U, Rong Q, Pfeifer K, Lang F (2005) KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl Acad Sci 102:17864–17869. doi: 10.1073/pnas.0505860102 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Whicher JR, MacKinnon R (2016) Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science 353:664–669. doi: 10.1126/science.aaf8070 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Neher E, Sakmann B (1976) Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature 260:799–802PubMedCrossRefGoogle Scholar
  13. 13.
    Armstrong CM, Bezanilla F (1973) Currents related to movement of the gating particles of the sodium channels. Nature 242:459–461PubMedCrossRefGoogle Scholar
  14. 14.
    Aggarwal SK, MacKinnon R (1996) Contribution of the S4 segment to gating charge in the Shaker K+ channel. Neuron 16:1169–1177. doi: 10.1016/S0896-6273(00)80143-9 PubMedCrossRefGoogle Scholar
  15. 15.
    Seoh S-A, Sigg D, Papazian DM, Bezanilla F (1996) Voltage-sensing residues in the S2 and S4 segments of the shaker K+ channel. Neuron 16:1159–1167. doi: 10.1016/S0896-6273(00)80142-7 PubMedCrossRefGoogle Scholar
  16. 16.
    Stefani E, Toro L, Perozo E, Bezanilla F (1994) Gating of shaker K+ channels: I. Ionic and gating currents. Biophys J 66:996–1010. doi: 10.1016/S0006-3495(94)80881-1 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Loussouarn G (2003) Phosphatidylinositol-4,5-bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K+ channels. EMBO J 22:5412–5421. doi: 10.1093/emboj/cdg526 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Tempel BL, Papazian DM, Schwarz TL, Jan YN, Jan LY (1987) Sequence of a probable potassium channel component encoded at Shaker locus of Drosophila. Science 237:770–775. doi: 10.1126/science.2441471 PubMedCrossRefGoogle Scholar
  19. 19.
    Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayama H, Kanaoka Y, Minamino N (1984) Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312:121–127PubMedCrossRefGoogle Scholar
  20. 20.
    Long SB (2005) Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309:903–908. doi: 10.1126/science.1116270 PubMedCrossRefGoogle Scholar
  21. 21.
    Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77PubMedCrossRefGoogle Scholar
  22. 22.
    del Camino D, Holmgren M, Liu Y, Yellen G (2000) Blocker protection in the pore of a voltage-gated K+ channel and its structural implications. Nature 403:321–325. doi: 10.1038/35002099 PubMedCrossRefGoogle Scholar
  23. 23.
    Beckstein O, Biggin PC, Bond P, Bright JN, Domene C, Grottesi A, Holyoake J, Sansom MS (2003) Ion channel gating: insights via molecular simulations. FEBS Lett 555:85–90. doi: 10.1016/S0014-5793(03)01151-7 PubMedCrossRefGoogle Scholar
  24. 24.
    Domene C, Haider S, Sansom MSP (2003) Ion channel structures: a review of recent progress. Curr Opin Drug Discov Devel 6:611–619PubMedGoogle Scholar
  25. 25.
    Broomand A, Männikkö R, Larsson HP, Elinder F (2003) Molecular movement of the voltage sensor in a K channel. J Gen Physiol 122:741–748. doi: 10.1085/jgp.200308927 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Neale EJ, Elliott DJS, Hunter M, Sivaprasadarao A (2003) Evidence for intersubunit interactions between S4 and S5 transmembrane segments of the shaker potassium channel. J Biol Chem 278:29079–29085. doi: 10.1074/jbc.M301991200/6493 PubMedCrossRefGoogle Scholar
  27. 27.
    Long SB, Tao X, Campbell EB, MacKinnon R (2007) Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450:376–382. doi: 10.1038/nature06265 PubMedCrossRefGoogle Scholar
  28. 28.
    Chen X, Wang Q, Ni F, Ma J (2010) Structure of the full-length Shaker potassium channel Kv1.2 by normal-mode-based X-ray crystallographic refinement. Proc Natl Acad Sci U S A 107:11352–11357. doi: 10.1073/pnas.1000142107 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vardanyan V, Pongs O (2012) Coupling of voltage-sensors to the channel pore: a comparative view. Front Pharmacol 3:145. doi: 10.3389/fphar.2012.00145 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ferrer T, Rupp J, Piper DR, Tristani-Firouzi M (2006) The S4-S5 linker directly couples voltage sensor movement to the activation gate in the human ether-a-go-go-related gene (hERG) K+ channel. J Biol Chem 281:12858–12864. doi: 10.1074/jbc.M513518200 PubMedCrossRefGoogle Scholar
  31. 31.
    Choveau FS, Rodriguez N, Ali FA, Labro AJ, Rose T, Dahimene S, Boudin H, Le Henaff C, Escande D, Snyders DJ, Charpentier F, Merot J, Baro I, Loussouarn G (2011) KCNQ1 channels voltage dependence through a voltage-dependent binding of the S4-S5 linker to the pore domain. J Biol Chem 286:707–716. doi: 10.1074/jbc.M110.146324 PubMedCrossRefGoogle Scholar
  32. 32.
    Choveau FS, Abderemane-Ali F, Coyan FC, Es-Salah-Lamoureux Z, Baró I, Loussouarn G (2012) Opposite effects of the S4–S5 linker and PIP2 on voltage-gated channel function: KCNQ1/KCNE1 and other channels. Front Pharmacol 3:125. doi: 10.3389/fphar.2012.00125 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Zaydman MA, Silva JR, Delaloye K, Li Y, Liang H, Larsson HP, Shi J, Cui J (2013) Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening. Proc Natl Acad Sci 110:13180–13185. doi: 10.1073/pnas.1305167110 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Zaydman MA, Kasimova MA, McFarland K, Beller Z, Hou P, Kinser HE, Liang H, Zhang G, Shi J, Tarek M et al (2014) Domain–domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel. Elife 3:e03606PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Smith JA, Vanoye CG, George AL, Meiler J, Sanders CR (2007) Structural models for the KCNQ1 voltage-gated potassium channel . Biochemistry (Mosc) 46:14141–14152. doi: 10.1021/bi701597s CrossRefGoogle Scholar
  36. 36.
    Xu Y, Wang Y, Meng X-Y, Zhang M, Jiang M, Cui M, Tseng G-N (2013) Building KCNQ1/KCNE1 channel models and probing their interactions by molecular-dynamics simulations. Biophys J 105:2461–2473. doi: 10.1016/j.bpj.2013.09.058 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kasimova MA, Zaydman MA, Cui J, Tarek M (2015) PIP2-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6. Sci Rep 5:7474. doi: 10.1038/srep07474 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pons J-L, Labesse G (2009) @TOME-2: a new pipeline for comparative modeling of protein-ligand complexes. Nucleic Acids Res 37:W485–W491. doi: 10.1093/nar/gkp368 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Cassarino TG, Bertoni M, Bordoli L, Schwede T (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:W252–W258. doi: 10.1093/nar/gku340 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Yu J, Picord G, Tuffery P, Guerois R (2015) HHalign-Kbest: exploring sub-optimal alignments for remote homology comparative modeling: Fig. 1. Bioinformatics 31:3850. doi: 10.1093/bioinformatics/btv441 PubMedGoogle Scholar
  41. 41.
    Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948. doi: 10.1093/bioinformatics/btm404 PubMedCrossRefGoogle Scholar
  43. 43.
    Krivov GG, Shapovalov MV, Dunbrack RL (2009) Improved prediction of protein side-chain conformations with SCWRL4. Proteins Struct Funct Bioinforma 77:778–795. doi: 10.1002/prot.22488 CrossRefGoogle Scholar
  44. 44.
    Webb B, Sali A (2014) Comparative protein structure modeling using MODELLER: comparative protein structure modeling using MODELLER. In: Bateman A, Pearson WR, Stein LD, Stormo GD, Yates JR (eds) Current protocal bioinformatics. John Wiley & Sons, Inc., Hoboken, NJ, pp 5.6.1–5.6.32CrossRefGoogle Scholar
  45. 45.
    Peng D, Kim J-H, Kroncke BM, Law CL, Xia Y, Droege KD, Van Horn WD, Vanoye CG, Sanders CR (2014) Purification and structural study of the voltage-sensor domain of the human KCNQ1 potassium ion channel. Biochemistry (Mosc) 53:2032–2042. doi: 10.1021/bi500102w CrossRefGoogle Scholar
  46. 46.
    Wu D, Delaloye K, Zaydman MA, Nekouzadeh A, Rudy Y, Cui J (2010) State-dependent electrostatic interactions of S4 arginines with E1 in S2 during Kv7.1 activation. J Gen Physiol 135:595–606. doi: 10.1085/jgp.201010408 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Wu D, Pan H, Delaloye K, Cui J (2010) KCNE1 remodels the voltage sensor of Kv7.1 to modulate channel function. Biophys J 99:3599–3608. doi: 10.1016/j.bpj.2010.10.018 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Shen M, Sali A (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15:2507–2524. doi: 10.1110/ps.062416606 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Morris AL, MacArthur MW, Hutchinson EG, Thornton JM (1992) Stereochemical quality of protein structure coordinates. Proteins Struct Funct Genet 12:345–364. doi: 10.1002/prot.340120407 PubMedCrossRefGoogle Scholar
  50. 50.
    Rohl CA, Strauss CEM, Chivian D, Baker D (2004) Modeling structurally variable regions in homologous proteins with rosetta. Proteins Struct Funct Bioinforma 55:656–677. doi: 10.1002/prot.10629 CrossRefGoogle Scholar
  51. 51.
    Raman S, Vernon R, Thompson J, Tyka M, Sadreyev R, Pei J, Kim D, Kellogg E, DiMaio F, Lange O, Kinch L, Sheffler W, Kim B-H, Das R, Grishin NV, Baker D (2009) Structure prediction for CASP8 with all-atom refinement using Rosetta. Proteins Struct Funct Bioinforma 77:89–99. doi: 10.1002/prot.22540 CrossRefGoogle Scholar
  52. 52.
    Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y (2015) The I-TASSER Suite: protein structure and function prediction. Nat Methods 12:7–8PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    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 U S A 103:7292–7297. doi: 10.1073/pnas.0602350103 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Allen MP, Tildesley DJ (1987) Computer simulation of liquids. Clarendon Press, OxfordGoogle Scholar
  55. 55.
    Leach AR (2001) Molecular modelling: principles and applications, 2nd edn. Prentice Hall, HarlowGoogle Scholar
  56. 56.
    Frenkel D, Smit B (2002) Understanding molecular simulation: from algorithms to applications, 2nd edn. Academic Press, San Diego, CAGoogle Scholar
  57. 57.
    Schuler LD, Daura X, van Gunsteren WF (2001) An improved GROMOS96 force field for aliphatic hydrocarbons in the condensed phase. J Comput Chem 22:1205–1218. doi: 10.1002/jcc.1078 CrossRefGoogle Scholar
  58. 58.
    MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiórkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins . J Phys Chem B 102:3586–3616. doi: 10.1021/jp973084f PubMedCrossRefGoogle Scholar
  59. 59.
    Ponder JW, Case DA (2003) Force fields for protein simulations. Adv Protein Chem 66:27–85PubMedCrossRefGoogle Scholar
  60. 60.
    Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236. doi: 10.1021/ja9621760 CrossRefGoogle Scholar
  61. 61.
    Jo S, Kim T, Iyer VG, Im W (2008) CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem 29:1859–1865. doi: 10.1002/jcc.20945 PubMedCrossRefGoogle Scholar
  62. 62.
    Wu EL, Cheng X, Jo S, Rui H, Song KC, Dávila-Contreras EM, Qi Y, Lee J, Monje-Galvan V, Venable RM, Klauda JB, Im W (2014) CHARMM-GUI Membrane Builder toward realistic biological membrane simulations. J Comput Chem 35:1997–2004. doi: 10.1002/jcc.23702 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Xu Y, Ramu Y, Lu Z (2008) Removal of phospho-head groups of membrane lipids immobilizes voltage sensors of K+ channels. Nature 451:826–829. doi: 10.1038/nature06618 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Zhang H, Craciun LC, Mirshahi T, Rohács T, Lopes CMB, Jin T, Logothetis DE (2003) PIP2 activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37:963–975. doi: 10.1016/S0896-6273(03)00125-9 PubMedCrossRefGoogle Scholar
  65. 65.
    Eckey K, Wrobel E, Strutz-Seebohm N, Pott L, Schmitt N, Seebohm G (2014) Novel Kv7.1-phosphatidylinositol 4,5-bisphosphate interaction sites uncovered by charge neutralization scanning. J Biol Chem 289:22749–22758. doi: 10.1074/jbc.M114.589796 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Shaw DE, Dror RO, Salmon JK, Grossman JP, Mackenzie KM, Bank JA, Young C, Deneroff MM, Batson B, Bowers KJ, Chow E, Eastwood MP, Ierardi DJ, Klepeis JL, Kuskin JS, Larson RH, Lindorff-Larsen K, Maragakis P, Moraes MA, Piana S, Shan Y, Towles B (2009) Millisecond-scale molecular dynamics simulations on anton. In: Proc. Conf. High Perform. Comput. Netw. Storage Anal. ACM, New York, NY, pp 39.1–39.11Google Scholar
  67. 67.
    Martyna GJ, Klein ML, Tuckerman M (1992) Nosé–Hoover chains: the canonical ensemble via continuous dynamics. J Chem Phys 97:2635–2643. doi: 10.1063/1.463940 CrossRefGoogle Scholar
  68. 68.
    Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545–1614. doi: 10.1002/jcc.21287 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688. doi: 10.1002/jcc.20290 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718. doi: 10.1002/jcc.20291 CrossRefGoogle Scholar
  71. 71.
    Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kalé L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802. doi: 10.1002/jcc.20289 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD et al (2006) Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proc. 2006 ACMIEEE Conf. Supercomput. ACM, New York, NY, p 84Google Scholar
  73. 73.
    Buck M, Bouguet-Bonnet S, Pastor RW, MacKerell AD (2006) Importance of the CMAP correction to the CHARMM22 protein force field: dynamics of hen lysozyme. Biophys J 90:L36–L38. doi: 10.1529/biophysj.105.078154 PubMedCrossRefGoogle Scholar
  74. 74.
    Suenaga A, Komeiji Y, Uebayasi M, Meguro T, Saito M, Yamato I (1998) Computational observation of an ion permeation through a channel protein. Biosci Rep 18:39–48. doi: 10.1023/A:1022292801256 PubMedCrossRefGoogle Scholar
  75. 75.
    Zhong Q, Jiang Q, Moore PB, Newns DM, Klein ML (1998) Molecular dynamics simulation of a synthetic ion channel. Biophys J 74:3–10. doi: 10.1016/S0006-3495(98)77761-6 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Tieleman DP, Biggin PC, Smith GR, Sansom MSP (2001) Simulation approaches to ion channel structure–function relationships. Q Rev Biophys 34:473–561. doi: 10.1017/S0033583501003729 PubMedCrossRefGoogle Scholar
  77. 77.
    Crozier PS, Henderson D, Rowley RL, Busath DD (2001) Model channel ion currents in NaCl-extended simple point charge water solution with applied-field molecular dynamics. Biophys J 81:3077–3089. doi: 10.1016/S0006-3495(01)75946-2 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Tarek M (2005) Membrane electroporation: a molecular dynamics simulation. Biophys J 88:4045–4053. doi: 10.1529/biophysj.104.050617 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Tieleman DP (2004) The molecular basis of electroporation. BMC Biochem 5:10. doi: 10.1186/1471-2091-5-10 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Gumbart J, Khalili-Araghi F, Sotomayor M, Roux B (2012) Constant electric field simulations of the membrane potential illustrated with simple systems. Biochim Biophys Acta 1818:294–302. doi: 10.1016/j.bbamem.2011.09.030 PubMedCrossRefGoogle Scholar
  81. 81.
    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:e1000289. doi: 10.1371/journal.pcbi.1000289 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Schow EV, Nizkorodov A, Freites JA, White SH, Tobias DJ (2010) Down-state model of the KvAP full channel. Biophys J 98:315a. doi: 10.1016/j.bpj.2009.12.1709 CrossRefGoogle Scholar
  83. 83.
    Jensen MØ, 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 PubMedCrossRefGoogle Scholar
  84. 84.
    Köpfer DA, Song C, Gruene T, Sheldrick GM, Zachariae U, de Groot BL (2014) Ion permeation in K+ channels occurs by direct Coulomb knock-on. Science 346:352–355. doi: 10.1126/science.1254840 PubMedCrossRefGoogle Scholar
  85. 85.
    Delemotte L, Tarek M, Klein ML, Amaral C, Treptow W (2011) Intermediate states of the Kv1. 2 voltage sensor from atomistic molecular dynamics simulations. Proc Natl Acad Sci 108:6109–6114PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Delemotte L, Dehez F, Treptow W, Tarek M (2008) Modeling membranes under a transmembrane potential. J Phys Chem B 112:5547–5550. doi: 10.1021/jp710846y PubMedCrossRefGoogle Scholar
  87. 87.
    Bostick D, Berkowitz ML (2003) The implementation of slab geometry for membrane-channel molecular dynamics simulations. Biophys J 85:97–107. doi: 10.1016/S0006-3495(03)74458-0 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Kutzner C, Grubmüller H, de Groot BL, Zachariae U (2011) Computational electrophysiology: the molecular dynamics of ion channel permeation and selectivity in atomistic detail. Biophys J 101:809–817. doi: 10.1016/j.bpj.2011.06.010 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(33–38):27–28Google Scholar
  90. 90.
    Perozo E, MacKinnon R, Bezanilla F, Stefani E (1993) Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels. Neuron 11:353–358PubMedCrossRefGoogle Scholar
  91. 91.
    Nonner W, Peyser A, Gillespie D, Eisenberg B (2004) Relating microscopic charge movement to macroscopic currents: the Ramo-Schockley theorem applied to ion channels. Biophys J 87:3716–3722PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Treptow W, Tarek M, Klein ML (2009) Initial response of the potassium channel voltage sensor to a transmembrane potential. J Am Chem Soc 131:2107–2109. doi: 10.1021/ja807330g PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Roux B (2008) The membrane potential and its representation by a constant electric field in computer simulations. Biophys J 95:4205–4216PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Sigworth FJ (1994) Voltage gating of ion channels. Q Rev Biophys 27:1–40PubMedCrossRefGoogle Scholar
  95. 95.
    Lecar H, Larsson HP, Grabe M (2003) Electrostatic model of S4 motion in voltage-gated ion channels. Biophys J 85:2854–2864PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Jogini V, Roux B (2007) Dynamics of the Kv1. 2 voltage-gated K+ channel in a membrane environment. Biophys J 93:3070–3082PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Islas LD, Sigworth FJ (2001) Electrostatic and the gating pore of Shaker potassium channels. J Gen Physiol 117:69–89PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Roux BT (1997) Influence of the membrane potential on the free energy of an intrinsic protein. Biophys J 73:2980–2989PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Grabe M, Lecar H, Jan YN, Jan LY (2004) A quantitative assessment of models for voltage-dependent gating ion channels. Proc Natl Acad Sci U S A 101:17640–17645PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ, Steinlein OK (2001) Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci 98:12272–12277. doi: 10.1073/pnas.211431298 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Lupoglazoff J-M, Denjoy I, Villain E, Fressart V, Simon F, Bozio A, Berthet M, Benammar N, Hainque B, Guicheney P (2004) Long QT syndrome in neonates. J Am Coll Cardiol 43:826–830. doi: 10.1016/j.jacc.2003.09.049 PubMedCrossRefGoogle Scholar
  102. 102.
    Millat G, Chevalier P, Restier-Miron L, Da Costa A, Bouvagnet P, Kugener B, Fayol L, Gonzàlez Armengod C, Oddou B, Chanavat V, Froidefond E, Perraudin R, Rousson R, Rodriguez-Lafrasse C (2006) Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet 70:214–227. doi: 10.1111/j.1399-0004.2006.00671.x PubMedCrossRefGoogle Scholar
  103. 103.
    Tombola F, Pathak MM, Gorostiza P, Isacoff EY (2006) The twisted ion-permeation pathway of a resting voltage-sensing domain. Nature 445:546–549. doi: 10.1038/nature05396 PubMedCrossRefGoogle Scholar
  104. 104.
    Tombola F, Pathak MM, Isacoff EY (2005) Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron 45:379–388PubMedCrossRefGoogle Scholar
  105. 105.
    Starace DM, Bezanilla F (2004) A proton pore in a potassium channel voltage sensor reveals a focused electric field. Nature 427:548–553. doi: 10.1038/nature02270 PubMedCrossRefGoogle Scholar
  106. 106.
    Starace DM, Bezanilla F (2001) Histidine scanning mutagenesis of basic residues of the S4 segment of the shaker potassium channel. J Gen Physiol 117:469–490PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    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:L72–L74. doi: 10.1016/j.bpj.2010.08.069 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Gamal El-Din TM, Heldstab H, Lehmann C, Greeff NG (2010) Double gaps along Shaker S4 demonstrate omega currents at three different closed states. Channels Austin TX 4:93–100CrossRefGoogle Scholar
  109. 109.
    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 102:258–267. doi: 10.1016/j.bpj.2011.10.057 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Audrey Deyawe
    • 1
  • Marina A. Kasimova
    • 1
  • Lucie Delemotte
    • 1
  • Gildas Loussouarn
    • 2
  • Mounir Tarek
    • 1
    • 3
    Email author
  1. 1.Structure et Réactivité des Systèmes Moléculaires Complexes, CNRSUniversité de LorraineNancyFrance
  2. 2.L’institut du thorax, Inserm, CNRSUniversité de NantesNantesFrance
  3. 3.CNRS, Unité Mixte de Recherches 7565Université de LorraineVandoeuvre-lès-NancyFrance

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