The seeming contradiction that K+ channels conduct K+ ions at maximal throughput rates while not permeating the slightly smaller Na+ ion 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 microseconds in length, which include over 7000 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 twodimensional infrared spectra of filter ion configurations.
Kopec, W., Köpfer, D. A., Vickery, O. N., Bondarenko, A. S., Jansen, T. L. C., De Groot, B. L., & Zachariae, U. (2018). Direct knock-on of desolvated ions governs strict ion selectivity in K+ channels. Nature Chemistry, 10(8), 813-820. https://doi.org/10.1038/s41557-018-0105-9