Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Energetics of ion conduction through the K+ channel

Nature volume 414, pages 73–77 (2001)Cite this article

Abstract

K+ channels are transmembrane proteins that are essential for the transmission of nerve impulses. The ability of these proteins to conduct K+ ions at levels near the limit of diffusion is traditionally described in terms of concerted mechanisms in which ion-channel attraction and ion–ion repulsion have compensating effects, as several ions are moving simultaneously in single file through the narrow pore1,2,3,4. The efficiency of such a mechanism, however, relies on a delicate energy balance—the strong ion-channel attraction must be perfectly counterbalanced by the electrostatic ion–ion repulsion. To elucidate the mechanism of ion conduction at the atomic level, we performed molecular dynamics free energy simulations on the basis of the X-ray structure of the KcsA K+ channel4. Here we find that ion conduction involves transitions between two main states, with two and three K+ ions occupying the selectivity filter, respectively; this process is reminiscent of the ‘knock-on’ mechanism proposed by Hodgkin and Keynes in 19551. The largest free energy barrier is on the order of 2–3 kcal mol-1, implying that the process of ion conduction is limited by diffusion. Ion–ion repulsion, although essential for rapid conduction, is shown to act only at very short distances. The calculations show also that the rapidly conducting pore is selective.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: Topographic free energy maps of ion conduction calculated from umbrella sampling molecular dynamics simulations.
Figure 3: Superposition of instantaneous dynamical configurations showing the dominant ion positions associated with the free energy minima in Fig. 2.
Figure 4: Importance of ion–ion repulsion on the elementary steps of ion conduction.

Similar content being viewed by others

References

  1. Hodgkin, A. L. & Keynes, R. D. The potassium permeability of a giant nerve fibre. J. Physiol. 128, 61–88 (1955).

    Article  CAS  Google Scholar 

  2. Hille, B. & Schwarz, W. Potassium channels as multi-ion single-file pores. J. Gen. Physiol. 72, 409–442 (1978).

    Article  CAS  Google Scholar 

  3. Neyton, J. & Miller, C. Discrete Ba2+ block as a probe of ion occupancy and pore structure in the high-conductance Ca2+-activated K+ channel. J. Gen. Physiol. 92, 569–586 (1988).

    Article  CAS  Google Scholar 

  4. Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998).

    Article  ADS  CAS  Google Scholar 

  5. Roux, B. & MacKinnon, R. The cavity and pore helices in the KcsA K+ channel: electrostatic stabilization of monovalent cations. Science 285, 100–102 (1999).

    Article  CAS  Google Scholar 

  6. Karplus, M. & Petsko, G. A. Molecular dynamics simulations in biology. Nature 347, 631–639 (1990).

    Article  ADS  CAS  Google Scholar 

  7. Guidoni, L., Torre, V. & Carloni, P. Potassium and sodium binding to the outer mouth of the K+ channel. Biochem. 38, 8599–8604 (1999).

    Article  CAS  Google Scholar 

  8. Shrivastava, I. H. & Sansom, M. S. Simulations of ion permeation through a potassium channel: molecular dynamics of KcsA in a phospholipid bilayer. Biophys. J. 78, 557–570 (2000).

    Article  CAS  Google Scholar 

  9. Allen, T. W., Bliznyuk, A., Rendell, A. P., Kuyucak, S. & Chung, S. H. The potassium channel: structure, selectivity and diffusion. J. Chem. Phys. 112, 8191–8204 (2000).

    Article  ADS  CAS  Google Scholar 

  10. Aqvist, J. & Luzhkov, V. Ion permeation mechanism of the potassium channel. Nature 404, 881–884 (2000).

    Article  ADS  CAS  Google Scholar 

  11. Bernèche, S. & Roux, B. Molecular dynamics of the KcsA K(+) channel in a bilayer membrane. Biophys. J. 78, 2900–2917 (2000).

    Article  Google Scholar 

  12. Kirkwood, J. G. Statistical mechanics of fluid mixtures. J. Chem. Phys. 3, 300–313 (1935).

    Article  ADS  CAS  Google Scholar 

  13. Roux, B. Statistical mechanical equilibrium theory of selective ion channels. Biophys. J. 77, 139–153 (1999).

    Article  ADS  CAS  Google Scholar 

  14. Torrie, G. M. & Valleau, J. P. Nonphysical sampling distributions in Monte Carlo free-energy estimation: umbrella sampling. J. Comp. Phys. 23, 187–199 (1977).

    Article  ADS  Google Scholar 

  15. Alcayaga, C., Cecchi, X., Alvarez, O. & Latorre, R. Streaming potential measurements in Ca2+-activated K+ channels from skeletal and smooth muscle. Coupling of ion and water fluxes. Biophys. J. 55, 367–371 (1989).

    Article  CAS  Google Scholar 

  16. Schumaker, M. F. & MacKinnon, R. A simple model for multi-ion permeation. single-vacancy conduction in a simple pore model. Biophys. J. 58, 975–984 (1990).

    Article  CAS  Google Scholar 

  17. Armstrong, C. M. Induced inactivation of the potassium permeability of squid axon membranes. Nature 219, 1262–1263 (1968).

    Article  ADS  CAS  Google Scholar 

  18. Crouzy, S., Berneche, S. & Roux, B. Extracellular blockade of K+ channels by TEA: results from molecular dynamics simulations of the KcsA channel. J. Gen. Physiol. 118, 207–218 (2001).

    Article  CAS  Google Scholar 

  19. Eisenman, G. Cation selective electrodes and their mode of operation. Biophys. J. 2 (Suppl. 2), 259–323 (1962).

    Article  ADS  CAS  Google Scholar 

  20. Kollman, P. A. Free energy calculations: applications to chemical and biochemical phenomena. Chem. Rev. 93, 2395–2417 (1993).

    Article  CAS  Google Scholar 

  21. Perozo, E., MacKinnon, R., Bezanilla, F. & Stefani, E. Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels. Neuron 11, 353–358 (1993).

    Article  CAS  Google Scholar 

  22. Lauger, P. A channel mechanism for electrogenic ion pumps. Biochim. Biophys. Acta 552, 143–161 (1979).

    Article  CAS  Google Scholar 

  23. Brooks, B. R. et al. CHARMM: a program for macromolecular energy minimization and dynamics calculations. J. Comput. Chem. 4, 187–217 (1983).

    Article  CAS  Google Scholar 

  24. Essmann, U. et al. A smooth particle mesh Ewald method. J. Chem. Phys. 103, 8577–8593 (1995).

    Article  ADS  CAS  Google Scholar 

  25. Feller, S. E., Zhang, Y. H., Pastor, R. W. & Brooks, B. R. Constant pressure molecular dynamics simulation—the Langevin piston method. J. Chem. Phys. 103, 4613–4621 (1995).

    Article  ADS  CAS  Google Scholar 

  26. MacKerell, A. D. Jr et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998).

    Article  CAS  Google Scholar 

  27. Schlenkrich, M. J., Brickmann, J., MacKerell, A. D. Jr & Karplus, M. in Biological Membranes. A Molecular Perspective from Computation and Experiment (eds Merz, K. M. & Roux, B.) 31–81 (Birkhauser, Boston, 1996).

    Google Scholar 

  28. Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).

    Article  ADS  CAS  Google Scholar 

  29. Beglov, D. & Roux, B. Finite representation of an infinite bulk system: solvent boundary potential for computer simulations. J. Chem. Phys. 100, 9050–9063 (1994).

    Article  ADS  CAS  Google Scholar 

  30. Kumar, S., Bouzida, D., Swendsen, R. H., Kollman, P. A. & Rosenberg, J. M. The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J. Comp. Chem. 13, 1011–1021 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Discussions with R. MacKinnon and J. Cabral are gratefully acknowledged. This work was supported by the National Institutes of Health and by the Canadian Institutes of Health Research. Several calculations were performed at the RQCHP Computer Center of the University of Montreal and at the National Center for Supercomputing Applications (NCSA) of the University of Illinois at Urbana-Champaign. We are grateful to B. Lorazo for his support. All the molecular pictures were drawn with DINO (A. Philippsen).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, 10021, New York, USA

    Simon Bernèche & Benoît Roux

  2. Département de Physique, Université de Montréal, Montréal, H3C 3J7, Québec, Canada

    Simon Bernèche & Benoît Roux

Authors
  1. Simon Bernèche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benoît Roux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benoît Roux.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernèche, S., Roux, B. Energetics of ion conduction through the K+ channel. Nature 414, 73–77 (2001). https://doi.org/10.1038/35102067

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35102067

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing