Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Oct;83(4):1867–1876. doi: 10.1016/S0006-3495(02)73951-9

Open-state models of a potassium channel.

Philip C Biggin 1, Mark S P Sansom 1
PMCID: PMC1302279  PMID: 12324408

Abstract

The structure of the bacterial potassium channel, KcsA, corresponds to the channel in a closed state. Two lines of evidence suggest that the channel must widen its intracellular mouth when in an open state: 1) internal block by a series of tetraalkylammonium ions and 2) spin labeling experiments. Thus it is known that the protein moves in this region, but it is unclear by how much and the mechanisms that are involved. To address this issue we have applied a novel approach to generate plausible open-state models of KcsA. The approach can be thought of as placing a balloon inside the channel and gradually inflating it. Only the protein sees the balloon, and so water is free to move in and out of the channel. The balloon is a van der Waals sphere whose parameters change by a small amount at each time step, an approach similar to methods used in free energy perturbation calculations. We show that positioning of this balloon at various positions along the pore axis generates similar open-state models, thus indicating that there may be a preferred pathway to an open state. We also show that the resulting structures from this process are conformationally unstable and need to undergo a relaxation process for up to 4 ns. We show that the channel can relax into a new state that has a larger pore radius at the region of the intracellular mouth. The resulting models may be useful in exploring models of the channel in the context of ion permeation and blocking agents.

Full Text

The Full Text of this article is available as a PDF (358.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARMSTRONG C. M., BINSTOCK L. ANOMALOUS RECTIFICATION IN THE SQUID GIANT AXON INJECTED WITH TETRAETHYLAMMONIUM CHLORIDE. J Gen Physiol. 1965 May;48:859–872. doi: 10.1085/jgp.48.5.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allen T. W., Chung S. H. Brownian dynamics study of an open-state KcsA potassium channel. Biochim Biophys Acta. 2001 Dec 1;1515(2):83–91. doi: 10.1016/s0005-2736(01)00395-9. [DOI] [PubMed] [Google Scholar]
  3. Aqvist J., Luzhkov V. Ion permeation mechanism of the potassium channel. Nature. 2000 Apr 20;404(6780):881–884. doi: 10.1038/35009114. [DOI] [PubMed] [Google Scholar]
  4. Armstrong C. M. A closer picture of the K channel gate from ion trapping experiments. J Gen Physiol. 1997 May;109(5):523–524. doi: 10.1085/jgp.109.5.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Armstrong C. M. Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol. 1971 Oct;58(4):413–437. doi: 10.1085/jgp.58.4.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bernèche S., Roux B. Molecular dynamics of the KcsA K(+) channel in a bilayer membrane. Biophys J. 2000 Jun;78(6):2900–2917. doi: 10.1016/S0006-3495(00)76831-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Biggin P. C., Smith G. R., Shrivastava I., Choe S., Sansom M. S. Potassium and sodium ions in a potassium channel studied by molecular dynamics simulations. Biochim Biophys Acta. 2001 Feb 9;1510(1-2):1–9. doi: 10.1016/s0005-2736(00)00345-x. [DOI] [PubMed] [Google Scholar]
  8. Chapman M. L., Krovetz H. S., VanDongen A. M. GYGD pore motifs in neighbouring potassium channel subunits interact to determine ion selectivity. J Physiol. 2001 Jan 1;530(Pt 1):21–33. doi: 10.1111/j.1469-7793.2001.0021m.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cortes D. M., Cuello L. G., Perozo E. Molecular architecture of full-length KcsA: role of cytoplasmic domains in ion permeation and activation gating. J Gen Physiol. 2001 Feb;117(2):165–180. doi: 10.1085/jgp.117.2.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Doyle D. A., Morais Cabral J., Pfuetzner R. A., Kuo A., Gulbis J. M., Cohen S. L., Chait B. T., MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998 Apr 3;280(5360):69–77. doi: 10.1126/science.280.5360.69. [DOI] [PubMed] [Google Scholar]
  11. Flynn G. E., Zagotta W. N. Conformational changes in S6 coupled to the opening of cyclic nucleotide-gated channels. Neuron. 2001 Jun;30(3):689–698. doi: 10.1016/s0896-6273(01)00324-5. [DOI] [PubMed] [Google Scholar]
  12. Forrest L. R., Sansom M. S. Membrane simulations: bigger and better? Curr Opin Struct Biol. 2000 Apr;10(2):174–181. doi: 10.1016/s0959-440x(00)00066-x. [DOI] [PubMed] [Google Scholar]
  13. Grubmüller H., Heymann B., Tavan P. Ligand binding: molecular mechanics calculation of the streptavidin-biotin rupture force. Science. 1996 Feb 16;271(5251):997–999. doi: 10.1126/science.271.5251.997. [DOI] [PubMed] [Google Scholar]
  14. Guidoni L., Torre V., Carloni P. Potassium and sodium binding to the outer mouth of the K+ channel. Biochemistry. 1999 Jul 6;38(27):8599–8604. doi: 10.1021/bi990540c. [DOI] [PubMed] [Google Scholar]
  15. Hayward S., Berendsen H. J. Systematic analysis of domain motions in proteins from conformational change: new results on citrate synthase and T4 lysozyme. Proteins. 1998 Feb 1;30(2):144–154. [PubMed] [Google Scholar]
  16. Hayward S., Kitao A., Berendsen H. J. Model-free methods of analyzing domain motions in proteins from simulation: a comparison of normal mode analysis and molecular dynamics simulation of lysozyme. Proteins. 1997 Mar;27(3):425–437. doi: 10.1002/(sici)1097-0134(199703)27:3<425::aid-prot10>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  17. Heginbotham L., LeMasurier M., Kolmakova-Partensky L., Miller C. Single streptomyces lividans K(+) channels: functional asymmetries and sidedness of proton activation. J Gen Physiol. 1999 Oct;114(4):551–560. doi: 10.1085/jgp.114.4.551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Humphrey W., Dalke A., Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996 Feb;14(1):33-8, 27-8. doi: 10.1016/0263-7855(96)00018-5. [DOI] [PubMed] [Google Scholar]
  19. Isralewitz B., Gao M., Schulten K. Steered molecular dynamics and mechanical functions of proteins. Curr Opin Struct Biol. 2001 Apr;11(2):224–230. doi: 10.1016/s0959-440x(00)00194-9. [DOI] [PubMed] [Google Scholar]
  20. Jiang Youxing, Lee Alice, Chen Jiayun, Cadene Martine, Chait Brian T., MacKinnon Roderick. Crystal structure and mechanism of a calcium-gated potassium channel. Nature. 2002 May 30;417(6888):515–522. doi: 10.1038/417515a. [DOI] [PubMed] [Google Scholar]
  21. Jiang Youxing, Lee Alice, Chen Jiayun, Cadene Martine, Chait Brian T., MacKinnon Roderick. The open pore conformation of potassium channels. Nature. 2002 May 30;417(6888):523–526. doi: 10.1038/417523a. [DOI] [PubMed] [Google Scholar]
  22. Johnson J. P., Jr, Zagotta W. N. Rotational movement during cyclic nucleotide-gated channel opening. Nature. 2001 Aug 30;412(6850):917–921. doi: 10.1038/35091089. [DOI] [PubMed] [Google Scholar]
  23. Kabsch W., Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983 Dec;22(12):2577–2637. doi: 10.1002/bip.360221211. [DOI] [PubMed] [Google Scholar]
  24. LeMasurier M., Heginbotham L., Miller C. KcsA: it's a potassium channel. J Gen Physiol. 2001 Sep;118(3):303–314. doi: 10.1085/jgp.118.3.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Liu Y. S., Sompornpisut P., Perozo E. Structure of the KcsA channel intracellular gate in the open state. Nat Struct Biol. 2001 Oct;8(10):883–887. doi: 10.1038/nsb1001-883. [DOI] [PubMed] [Google Scholar]
  26. Lu T., Ting A. Y., Mainland J., Jan L. Y., Schultz P. G., Yang J. Probing ion permeation and gating in a K+ channel with backbone mutations in the selectivity filter. Nat Neurosci. 2001 Mar;4(3):239–246. doi: 10.1038/85080. [DOI] [PubMed] [Google Scholar]
  27. MacKinnon R., Cohen S. L., Kuo A., Lee A., Chait B. T. Structural conservation in prokaryotic and eukaryotic potassium channels. Science. 1998 Apr 3;280(5360):106–109. doi: 10.1126/science.280.5360.106. [DOI] [PubMed] [Google Scholar]
  28. Meuser D., Splitt H., Wagner R., Schrempf H. Exploring the open pore of the potassium channel from Streptomyces lividans. FEBS Lett. 1999 Dec 3;462(3):447–452. doi: 10.1016/s0014-5793(99)01579-3. [DOI] [PubMed] [Google Scholar]
  29. Miller C. See potassium run. Nature. 2001 Nov 1;414(6859):23–24. doi: 10.1038/35102126. [DOI] [PubMed] [Google Scholar]
  30. Morais-Cabral J. H., Zhou Y., MacKinnon R. Energetic optimization of ion conduction rate by the K+ selectivity filter. Nature. 2001 Nov 1;414(6859):37–42. doi: 10.1038/35102000. [DOI] [PubMed] [Google Scholar]
  31. Perozo E., Cortes D. M., Cuello L. G. Structural rearrangements underlying K+-channel activation gating. Science. 1999 Jul 2;285(5424):73–78. doi: 10.1126/science.285.5424.73. [DOI] [PubMed] [Google Scholar]
  32. Perozo E., Cortes D. M., Cuello L. G. Three-dimensional architecture and gating mechanism of a K+ channel studied by EPR spectroscopy. Nat Struct Biol. 1998 Jun;5(6):459–469. doi: 10.1038/nsb0698-459. [DOI] [PubMed] [Google Scholar]
  33. Roux B., Bernèche S., Im W. Ion channels, permeation, and electrostatics: insight into the function of KcsA. Biochemistry. 2000 Nov 7;39(44):13295–13306. doi: 10.1021/bi001567v. [DOI] [PubMed] [Google Scholar]
  34. Roux B., MacKinnon R. The cavity and pore helices in the KcsA K+ channel: electrostatic stabilization of monovalent cations. Science. 1999 Jul 2;285(5424):100–102. doi: 10.1126/science.285.5424.100. [DOI] [PubMed] [Google Scholar]
  35. Sansom M. S., Weinstein H. Hinges, swivels and switches: the role of prolines in signalling via transmembrane alpha-helices. Trends Pharmacol Sci. 2000 Nov;21(11):445–451. doi: 10.1016/s0165-6147(00)01553-4. [DOI] [PubMed] [Google Scholar]
  36. Shrivastava I. H., Capener C. E., Forrest L. R., Sansom M. S. Structure and dynamics of K channel pore-lining helices: a comparative simulation study. Biophys J. 2000 Jan;78(1):79–92. doi: 10.1016/S0006-3495(00)76574-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Shrivastava I. H., Sansom M. S. Simulations of ion permeation through a potassium channel: molecular dynamics of KcsA in a phospholipid bilayer. Biophys J. 2000 Feb;78(2):557–570. doi: 10.1016/S0006-3495(00)76616-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shrivastava Indira H., Sansom Mark S. P. Molecular dynamics simulations and KcsA channel gating. Eur Biophys J. 2002 Mar 15;31(3):207–216. doi: 10.1007/s00249-002-0209-3. [DOI] [PubMed] [Google Scholar]
  39. Smart O. S., Breed J., Smith G. R., Sansom M. S. A novel method for structure-based prediction of ion channel conductance properties. Biophys J. 1997 Mar;72(3):1109–1126. doi: 10.1016/S0006-3495(97)78760-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Smart O. S., Goodfellow J. M., Wallace B. A. The pore dimensions of gramicidin A. Biophys J. 1993 Dec;65(6):2455–2460. doi: 10.1016/S0006-3495(93)81293-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Smart O. S., Neduvelil J. G., Wang X., Wallace B. A., Sansom M. S. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J Mol Graph. 1996 Dec;14(6):354-60, 376. doi: 10.1016/s0263-7855(97)00009-x. [DOI] [PubMed] [Google Scholar]
  42. Wriggers W., Schulten K. Protein domain movements: detection of rigid domains and visualization of hinges in comparisons of atomic coordinates. Proteins. 1997 Sep;29(1):1–14. [PubMed] [Google Scholar]
  43. Zhou M., Morais-Cabral J. H., Mann S., MacKinnon R. Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors. Nature. 2001 Jun 7;411(6838):657–661. doi: 10.1038/35079500. [DOI] [PubMed] [Google Scholar]
  44. del Camino D., Holmgren M., Liu Y., Yellen G. Blocker protection in the pore of a voltage-gated K+ channel and its structural implications. Nature. 2000 Jan 20;403(6767):321–325. doi: 10.1038/35002099. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES