The seeming contradiction that K+ channels conduct K+ ions at maximal throughput rates while not permeating slightly smaller Na+ ions has perplexed scientists for decades. Although numerous models have addressed selective permeation in K+ channels, the combination of conduction efficiency and ion selectivity has not yet been linked through a unified functional model. Here, we investigate the mechanism of ion selectivity through atomistic simulations totalling more than 400 μs in length, which include over 7,000 permeation events. Together with free-energy calculations, our simulations show that both rapid permeation of K+ and ion selectivity are ultimately based on a single principle: the direct knock-on of completely desolvated ions in the channels’ selectivity filter. Herein, the strong interactions between multiple ‘naked’ ions in the four filter binding sites give rise to a natural exclusion of any competing ions. Our results are in excellent agreement with experimental selectivity data, measured ion interaction energies and recent two-dimensional infrared spectra of filter ion configurations.
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We thank H. Grubmüller, S. Bernèche, F. Heer and S. Llabrés for helpful discussions. This work was supported by the German Research Foundation through FOR 2518 ‘DynIon’, Project P5 (to W.K. and B.L.d.G), the Scottish Universities’ Physics Alliance (to U.Z.) and BBSRC training grant BB/J013072/1 (to O.N.V. and U.Z.). All data and analysis scripts are archived at the Max Planck Institute for Biophysical Chemistry archives and are available upon request.
Supplementary Methods, Supplementary simulation data, Supplementary Figures 1–14 and Supplementary Tables 1–11
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