Abstract
Potassium channels are essential for maintaining a normal ionic balance across cell membranes. Central to this function is the ability of such channels to support transmembrane ion conduction at nearly diffusion-limited rates while discriminating for K+ over Na+ by more than a thousand-fold. This selectivity arises because the transfer of the K+ ion into the channel pore is energetically favoured, a feature commonly attributed to a structurally precise fit between the K+ ion and carbonyl groups lining the rigid and narrow pore1. But proteins are relatively flexible structures2,3 that undergo rapid thermal atomic fluctuations larger than the small difference in ionic radius between K+ and Na+. Here we present molecular dynamics simulations for the potassium channel KcsA, which show that the carbonyl groups coordinating the ion in the narrow pore are indeed very dynamic (‘liquid-like’) and that their intrinsic electrostatic properties control ion selectivity. This finding highlights the importance of the classical concept of field strength4. Selectivity for K+ is seen to emerge as a robust feature of a flexible fluctuating pore lined by carbonyl groups.
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References
Hille, B., Armstrong, C. M. & MacKinnon, R. Ion channels: From idea to reality. Nature Med. 5, 1105–1109 (1999)
Zaccai, G. How soft is a protein? A protein dynamics force constant measured by neutron scattering. Science 288, 1604–1609 (2000)
Karplus, M. & Petsko, G. A. Molecular dynamics simulations in biology. Nature 347, 631–639 (1990)
Eisenman, G. Cation selective electrodes and their mode of operation. Biophys. J. 2, 259–323 (1962)
Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998)
Morais-Cabral, J. H., Zhou, Y. F. & MacKinnon, R. Energetic optimization of ion conduction rate by the K+ selectivity filter. Nature 414, 37–42 (2001)
Zhou, Y., Morais-Cabral, J. H., Kaufman, A. & MacKinnon, R. Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 Å resolution. Nature 414, 43–48 (2001)
Eisenman, G. & Horn, R. Ion selectivity revisited: the role of kinetic and equilibrium processes in ion permeation through channels. J. Membr. Biol. 76, 197–225 (1983)
Latorre, R. & Miller, C. Conduction and selectivity in potassium channels. J. Membr. Biol. 71, 11–30 (1983)
Hille, B. Ion Channels of Excitable Membranes 3rd edn (Sinauer, Sunderland, Massachusetts, 2001)
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, 569–596 (1988)
LeMasurier, M., Heginbotham, L. & Miller, C. KscA: it's a potassium channel. J. Gen. Physiol. 118, 303–314 (2001)
Nimigean, C. M. & Miller, C. Na+ block and permeation in K+ channel of known structure. J. Gen. Physiol. 120, 323–325 (2002)
Pauling, L. Nature of the Chemical Bond and Structure of Molecules and Crystals 3rd edn (Cornell Univ. Press, Ithaca, 1960)
Allen, T. W., Andersen, O. S. & Roux, B. On the importance of atomic fluctuations, protein flexibility and solvent in ion permeation. J. Gen. Physiol. (in the press)
Åqvist, J. & Luzhkov, V. Ion permeation mechanism of the potassium channel. Nature 404, 881–884 (2000)
Luzhkov, V. B. & Åqvist, J. K+/Na+ selectivity of the KcsA potassium channel from microscopic free energy perturbation calculations. Biochim. Biophys. Acta 1548, 194–202 (2001)
Allen, T. W., Bliznyuk, A., Rendell, A. P., Kyuucak, S. & Chung, S. H. The potassium channel: Structure, selectivity and diffusion. J. Chem. Phys. 112, 8191–8204 (2000)
Bernèche, S. & Roux, B. Energetics of ion conduction through the K+ channel. Nature 414, 73–77 (2001)
Bernèche, S. & Roux, B. A microscopic view of ion conduction through the K+ channel. Proc. Natl Acad. Sci. USA 100, 8644–8648 (2003)
Shrivastava, I. H., Tieleman, D. P., Biggin, P. C. & Sansom, M. S. P. K+ versus Na+ ions in a K channel selectivity filter: A simulation study. Biophys. J. 83, 633–645 (2002)
Guidoni, L., Torre, V. & Carloni, P. Potassium and sodium binding to the outer mouth of the K+ channe. Biochemistry 38, 8599–8604 (1999)
Loboda, A., Melishchuk, A. & Armstrong, C. Dilated and defunct K channels in the absence of K+. Biophys. J. 80, 2704–2714 (2001)
Zhou, Y. F. & MacKinnon, R. The occupancy of ions in the K+ selectivity filter: Charge balance and coupling of ion binding to a protein conformational change underlie high conduction rates. J. Mol. Biol. 333, 965–975 (2003)
Yamashita, M. M., Wesson, L., Eisenman, G. & Eisenberg, D. Where metal ions bind in proteins. Proc. Natl Acad. Sci. USA 87, 5648–5652 (1990)
Åqvist, J., Alvarez, O. & Eisenman, G. Ion-selective properties of a small ionophore in methanol studied by free energy perturbation simulations. J. Phys. Chem. 96, 10019–10025 (1992)
Marrone, T. J. & Merz, K. M. Jr. Molecular recognition of K+ and Na+ by valinomycin in methanol. J. Am. Chem. Soc. 117, 779–791 (1995)
MacKerell, A. D. J. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998)
Weeks, J. D., Chandler, D. & Andersen, H. C. Role of repulsive forces in determining the equilibrium structure of simple liquids. J. Chem. Phys. 54, 5237–5247 (1971)
Lu, T. et al. Probing ion permeation and gating in a K+ channel with backbone mutations in the selectivity filter. Nature Neurosci. 4, 239–246 (2001)
Heinemann, S. H., Terlau, H., Stuhmer, W., Imoto, K. & Numa, S. Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356, 441–443 (1992)
Brooks, B. R. et al. CHARMM: a program for macromolecular energy minimization and dynamics calculations. J. Comput. Chem. 4, 187–217 (1983)
Acknowledgements
Discussions with G. Eisenman, J. Åqvist, O. Andersen, C. Miller and D. Doyle are gratefully acknowledged. This work was funded by the NIH and by the American Epilepsy Society and UCB Pharma Inc. to S.Yu.N. This work was supported by the National Center for Supercomputing Applications (NCSA) at the University of Illinois, Urbana-Champaign, the Pittsburgh Supercomputing Center (PSC), and the Scientific Computing and Visualization (SCV) group at Boston University.
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Supplementary Information
Contains an analysis of the crystallographic B-factors of the KcsA channel from the data of Zhou et al. (2001) and compares with the results from molecular dynamics. It also provides more information about the computational methods used and shows snapshots of K+ solvated in liquid NMA, valinomycin, as well as in the model-binding site with freely-fluctuating carbonyls. (PDF 286 kb)
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Noskov, S., Bernèche, S. & Roux, B. Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands. Nature 431, 830–834 (2004). https://doi.org/10.1038/nature02943
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DOI: https://doi.org/10.1038/nature02943
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