Ion channel gates: comparative analysis of energy barriers

  • Kaihsu Tai
  • Shozeb Haider
  • Alessandro Grottesi
  • Mark S. P. Sansom
Original Paper


The energetic profile of an ion translated along the axis of an ion channel should reveal whether the structure corresponds to a functionally open or closed state of the channel. In this study, we explore the combined use of Poisson–Boltzmann electrostatic calculations and evaluation of van der Waals interactions between ion and pore to provide an initial appraisal of the gating state of a channel. This approach is exemplified by its application to the bacterial inward rectifier potassium channel KirBac3.1, where it reveals the closed gate to be formed by a ring of leucine (L124) side chains. We have extended this analysis to a comparative survey of gating profiles, including model hydrophobic nanopores, the nicotinic acetylcholine receptor, and a number of potassium channel structures and models. This enables us to identify three gating regimes, and to show the limitation of this computationally inexpensive method. For a (closed) gate radius of 0.4 nm < R < 0.8 nm, a hydrophobic gate may be present. For a gate radius of 0.2 nm < R < 0.4 nm, both electrostatic and van der Waals interactions will contribute to the barrier height. Below R = 0.2 nm, repulsive van der Waals interactions are likely to dominate, resulting in a sterically occluded gate. In general, the method is more useful when the channel is wider; for narrower channels, the flexibility of the protein may allow otherwise-unsurmountable energetic barriers to be overcome.


Ion channel Gate Electrostatics Model Simulation 



Large-conductance mechanosensitive channel


Small-conductance mechanosensitive channel


Nicotinic acetylcholine receptor




Potential of mean force



We thank Shiva Amiri, Kia Balali-Mood, Oliver Beckstein, Phil Biggin, John Holyoake, and Phill Stansfeld for helpful discussions; Nathan Baker and Jens Erik Nielsen for the APBS and PDB2PQR software. This work is supported by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.


  1. Allen TW, Andersen OS, Roux B (2004) On the Importance of atomic fluctuations, protein flexibility, and solvent in ion permeation. J Gen Physiol 124:679–690. doi: 10.1085/jgp.200409111 PubMedCrossRefGoogle Scholar
  2. Amiri S, Tai K, Beckstein O, Biggin PC, Sansom MSP (2005) The a7 nicotinic acetylcholine receptor: molecular modelling, electrostatics, and energetics. Mol Membr Biol 22:151–162. doi: 10.1080/09687860500063340 PubMedCrossRefGoogle Scholar
  3. Anishkin A, Sukharev S (2004) Water dynamics and dewetting transitions in the small mechanosensitive channel MscS. Biophys J 86:2883–2895PubMedCrossRefGoogle Scholar
  4. Archer SL, Rusch NJ (2001) Potassium channels in cardiovascular biology. Kluwer Academic/Plenum Publishers, New York, p 899Google Scholar
  5. Ashcroft FM (2000) Ion channels and disease. Academic Press, San DiegoGoogle Scholar
  6. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci USA 98:10037–10041. doi: 10.1073/pnas.181342398 PubMedCrossRefGoogle Scholar
  7. Beckstein O, Sansom MSP (2003) Liquid–vapor oscillations of water in hydrophobic nanopores. Proc Natl Acad Sci USA 100:7063–7068. doi: 10.1073/pnas.1136844100 PubMedCrossRefGoogle Scholar
  8. Beckstein O, Sansom MSP (2004) The influence of geometry, surface character and flexibility on the permeation of ions and water through biological pores. Phys Biol 1:42–52. doi: 10.1088/1478-3967/1/1/005 PubMedCrossRefGoogle Scholar
  9. Beckstein O, Sansom MSP (2006) A hydrophobic gate in an ion channel: the closed state of the nicotinic acetylcholine receptor. Phys Biol 3:147–159. doi: 10.1088/1478-3975/3/2/007 PubMedCrossRefGoogle Scholar
  10. Beckstein O, Biggin PC, Sansom MSP (2001) A hydrophobic gating mechanism for nanopores. J Phys Chem B 105:12902–12905. doi: 10.1021/jp012233y CrossRefGoogle Scholar
  11. Beckstein O, Biggin PC, Bond PJ, Bright JN, Domene C, Grottesi A, Holyoake J, Sansom MSP (2003) Ion channel gating: insights via molecular simulations. FEBS Lett 555:85–90. doi: 10.1016/S0014-5793(03)01151-7 PubMedCrossRefGoogle Scholar
  12. Beckstein O, Tai K, Sansom MSP (2004) Not ions alone: barriers to ion permeation in nanopores and channels. J Am Chem Soc 126:14694–14695. doi: 10.1021/ja045271e PubMedCrossRefGoogle Scholar
  13. Berman H, Henrick K, Nakamura H (2003) Announcing the worldwide protein data bank. Nat Struct Biol 10:980. doi: 10.1038/nsb1203-980 PubMedCrossRefGoogle Scholar
  14. Boda D, Nonner W, Valiskó M, Henderson D, Eisenberg B, Gillespie D (2007) Steric selectivity in Na channels arising from protein polarization and mobile side chains. Biophys J 93:1960–1980. doi: 10.1529/biophysj.107.105478 PubMedCrossRefGoogle Scholar
  15. Bostick DL, Brooks CL (2007) Selectivity in K+ channels is due to topological control of the permanent ion’s coordinated state. Proc Natl Acad Sci USA 104:9260–9265. doi: 10.1073/pnas.0700554104 PubMedCrossRefGoogle Scholar
  16. Buchera D, Raugei S, Guidoni L, Dal Peraro M, Rothlisberger U, Carloni P, Klein ML (2006) Polarization effects and charge transfer in the KcsA potassium channel. Biophys Chem 124:292–301. doi: 10.1016/j.bpc.2006.04.008 CrossRefGoogle Scholar
  17. Chang G, Spencer RH, Lee AT, Barclay MT, Rees DC (1998) Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel. Science 282:2220–2226. doi: 10.1126/science.282.5397.2220 PubMedCrossRefGoogle Scholar
  18. Chung SH, Allen TW, Kuyucak S (2002) Modeling diverse range of potassium channels with brownian dynamics. Biophys J 83:263–277PubMedCrossRefGoogle Scholar
  19. Cordero-Morales JF, Cuello LG, Perozo E (2006a) Voltage-dependent gating at the KcsA selectivity filter. Nat Struct Mol Biol 13:319–322. doi: 10.1038/nsmb1070 PubMedCrossRefGoogle Scholar
  20. Cordero-Morales JF, Cuello LG, Zhao YX, Jogini V, Cortes DM, Roux B, Perozo E (2006b) Molecular determinants of gating at the potassium-channel selectivity filter. Nat Struct Mol Biol 13:311–318. doi: 10.1038/nsmb1069 PubMedCrossRefGoogle Scholar
  21. Corry B (2004) Theoretical conformation of the closed and open states of the acetylcholine receptor channel. Biochim Biophys Acta 1663:2–5. doi: 10.1016/j.bbamem.2004.02.006 PubMedCrossRefGoogle Scholar
  22. Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA (2004) PDB2PQR: an automated pipeline for the setup, execution, and analysis of Poisson–Boltzmann electrostatics calculations. Nucleic Acids Res 32:W665–W667. doi: 10.1093/nar/gkh381 PubMedCrossRefGoogle Scholar
  23. Doyle DA (2004) Structural themes in ion channels. Eur Biophys J 33:175–179. doi: 10.1007/s00249-003-0382-z PubMedCrossRefGoogle Scholar
  24. Doyle DA, Cabral JM, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Cahit BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77. doi: 10.1126/science.280.5360.69 PubMedCrossRefGoogle Scholar
  25. Edwards S, Corry B, Kuyucak S, Chung S-H (2002) Continuum electrostatics fails to describe ion permeation in the gramicidin channel. Biophys J 83:1348–1360PubMedCrossRefGoogle Scholar
  26. Fiser A, Kinh Gian Do R, Sali A (2000) Modeling of loops in protein structures. Protein Sci 9:1753–1773PubMedCrossRefGoogle Scholar
  27. Gouaux E, MacKinnon R (2005) Principles of selective ion transport in channels and pumps. Science 310:1461–1465. doi: 10.1126/science.1113666 PubMedCrossRefGoogle Scholar
  28. Haider S, Khalid S, Tucker S, Ashcroft FM, Sansom MSP (2007) Molecular dynamics simulations of inwardly rectifying (Kir) potassium channels: a comparative study. Biochemistry 46:3643–3652. doi: 10.1021/bi062210f PubMedCrossRefGoogle Scholar
  29. Hilf RJC, Dutzler R (2008) X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452:375–379. doi: 10.1038/nature06717 PubMedCrossRefGoogle Scholar
  30. Hille B (2001) Ionic channels of excitable membranes, 3rd edn. Sinauer Associates Inc, SunderlandGoogle Scholar
  31. Holyoake J, Domene C, Bright JN, Sansom MSP (2003) KcsA closed and open: modelling and simulation studies. Eur Biophys J 33:238–246PubMedGoogle Scholar
  32. Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1:727–730. doi: 10.1038/nrd892 PubMedCrossRefGoogle Scholar
  33. Humphrey W, Dalke A, Schulten K (1996) VMD––visual molecular dynamics. J Mol Graph 14:33–38. doi: 10.1016/0263-7855(96)00018-5 PubMedCrossRefGoogle Scholar
  34. Ivanov I, Cheng X, Sine SM, McCammon JA (2007) Barriers to ion translocation in cationic and anionic receptors from the Cys-loop family. J Am Chem Soc 129:8217–8224. doi: 10.1021/ja070778l PubMedCrossRefGoogle Scholar
  35. Jeanmougin F, Thompson JD, Gouy M, Higgins DG, Gibson TJ (1998) Multiple sequence alignment with clustal X. Trends Biochem Sci 23:403–405. doi: 10.1016/S0968-0004(98)01285-7 PubMedCrossRefGoogle Scholar
  36. Jogini V, Roux B (2005) Electrostatics of the intracellular vestibule of K+ channels. J Mol Biol 354:272–288. doi: 10.1016/j.jmb.2005.09.031 PubMedCrossRefGoogle Scholar
  37. Kong Y, Shen Y, Warth TE, Ma J (2002) Conformational pathways in the gating of Escherichia coli mechanosensitive channel. Proc Natl Acad Sci USA 99:5999–6004. doi: 10.1073/pnas.092051099 PubMedCrossRefGoogle Scholar
  38. Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA (2003) Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300:1922–1926. doi: 10.1126/science.1085028 PubMedCrossRefGoogle Scholar
  39. Kuo AL, Domene C, Johnson LN, Doyle DA, Venien-Bryan C (2005) Two different conformational states of the KirBac3.1 potassium channel revealed by electron crystallography. Structure 13:1463–1472. doi: 10.1016/j.str.2005.07.011 PubMedCrossRefGoogle Scholar
  40. MacKinnon R (2003) Potassium channels. FEBS Lett 555:62–65. doi: 10.1016/S0014-5793(03)01104-9 PubMedCrossRefGoogle Scholar
  41. MacKinnon R, Cohen SL, Kuo A, Lee A, Chait BT (1998) Structural conservation in prokaryotic and eukaryotic potassium channels. Science 280:106–109. doi: 10.1126/science.280.5360.106 PubMedCrossRefGoogle Scholar
  42. Maguire ME (2006) The structure of CorA: a Mg2+-selective channel. Curr Opin Struct Biol 16:432–438. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  43. Mamonov AB, Coalson RD, Nitzan A, Kurnikova MG (2003) The role of the dielectric barrier in narrow biological channels: a novel composite approach to modeling single-channel currents. Biophys J 84:3646–3661PubMedCrossRefGoogle Scholar
  44. Nishida M, Cadene M, Chait BT, MacKinnon R (2007) Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J 26:4005–4015. doi: 10.1038/sj.emboj.7601828 PubMedCrossRefGoogle Scholar
  45. Noskov SY, Roux B (2006) Ion selectivity in potassium channels. Biophys Chem 124:279–291. doi: 10.1016/j.bpc.2006.05.033 PubMedCrossRefGoogle Scholar
  46. Noskov SY, Bernèche S, Roux B (2004) Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands. Nature 431:830–834. doi: 10.1038/nature02943 PubMedCrossRefGoogle Scholar
  47. Rashin A, Honig B (1985) Reevaluation of the Born model of ion hydration. J Phys Chem 89:5588. doi: 10.1021/j100272a006 CrossRefGoogle Scholar
  48. Roth R, Gillespie D, Nonner W, Eisenberg R (2008) Bubbles, gating, and anaesthetics in ion channels. Biophys J 94:4282–4298. doi: 10.1529/biophysj.107.120493 PubMedCrossRefGoogle Scholar
  49. Roux B, Schulten K (2004) Computational studies of membrane channels. Structure 12:1343–1351. doi: 10.1016/j.str.2004.06.013 PubMedCrossRefGoogle Scholar
  50. Roux B, Allen T, Berneche S, Im W (2004) Theoretical and computational models of biological ion channels. Q Rev Biophys 37:15–103. doi: 10.1017/S0033583504003968 PubMedCrossRefGoogle Scholar
  51. Sali A, Blundell TL (1993) Comparative protein modeling by satisfaction of spatial restraints. J Mol Biol 234:779–815. doi: 10.1006/jmbi.1993.1626 PubMedCrossRefGoogle Scholar
  52. Shen YF, Kong YF, Ma JP (2002) Intrinsic flexibility and gating mechanism of the potassium channel KcsA. Proc Natl Acad Sci USA 99:1949–1953. doi: 10.1073/pnas.042650399 PubMedCrossRefGoogle Scholar
  53. Shi N, Ye S, Alam A, Chen L, Jiang Y (2006) Atomic structure of a Na+- and K+-conducting channel. Nature 440:570–574. doi: 10.1038/nature04508 PubMedCrossRefGoogle Scholar
  54. Shrivastava IH, Bahar I (2006) Common mechanism of pore opening shared by five different potassium channels. Biophys J 90:3929–3940. doi: 10.1529/biophysj.105.080093 PubMedCrossRefGoogle Scholar
  55. Smart OS, Neduvelil JG, Wang X, Wallace BA, Sansom MSP (1996) Hole: a program for the analysis of the pore dimensions of ion channel structural models. J Mol Graph 14:354–360. doi: 10.1016/S0263-7855(97)00009-X PubMedCrossRefGoogle Scholar
  56. 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 PubMedGoogle Scholar
  57. van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718. doi: 10.1002/jcc.20291 CrossRefGoogle Scholar
  58. Woolf TB, Zuckerman DM, Lua N, Jang H (2004) Tools for channels: moving towards molecular calculations of gating and permeation in ion channel biophysics. J Mol Graph Model 22:359–368. doi: 10.1016/j.jmgm.2003.12.003 PubMedCrossRefGoogle Scholar
  59. Yu FH, Yarov-Yarovoy V, Gutman GA, Catterall WA (2005) Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol Rev 57:387–395. doi: 10.1124/pr.57.4.13 PubMedCrossRefGoogle Scholar

Copyright information

© European Biophysical Societies' Association 2008

Authors and Affiliations

  • Kaihsu Tai
    • 1
  • Shozeb Haider
    • 1
    • 2
  • Alessandro Grottesi
    • 1
    • 3
  • Mark S. P. Sansom
    • 1
  1. 1.Department of BiochemistryUniversity of OxfordOxfordUK
  2. 2.Cancer Research UK Biomolecular Structure Group, Department of Pharmaceutical and Biological Chemistry, The School of PharmacyUniversity of LondonLondonUK
  3. 3.CASPUR Consorzio Interuniversitario per le Applicazioni del Supercalcolo per Università e RicercaRomeItaly

Personalised recommendations