Direct knock-on of desolvated ions governs strict ion selectivity in K+ channels

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. That K + channels conduct K + ions at near-diffusion limited rates, but block the passage of smaller Na + ions, creates an apparent contradiction. Now, atomistic simulations and free-energy calculations are used to show that both K + permeation and ion selectivity are governed by the direct knock-on of completely desolvated ions in the channels’ selectivity filter.