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Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands

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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Figure 1: Schematic structure of the cation binding sites in the selectivity filter of the KcsA channel7.
Figure 2: Ion–carbonyl oxygen pair correlation function ρ(r) and coordination number n(r) in different environments.
Figure 3: Selectivity of a model of the KcsA binding site S2 as a function of flexibility.
Figure 4: Intrinsic selectivity of a simple model of freely fluctuating carbonyl-like dipoles.

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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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Correspondence to Benoît Roux.

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Supplementary information

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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