Regulation of ion Permeation in the Selectivity Filter of Potassium Channels

Abstract

Ion efflux through potassium channels is regulated by a main gate controlled by ligands and/or the transmembrane voltage. The opening of the main gate let K ions flow down their gradient, diffusing through the selectivity filter of the channel, which can also contribute to the regulation of the ionic current by changing its conformation. Functional and structural data have brought evidence of interaction between the main gate and the selectivity filter of potassium channels. It is understood that opening the main gate favors the inactivated state of the filter, whereas closing the main gate stabilize the conducting state of the filter.We have performed molecular dynamics simulations and potential of mean force calculations showing that the selectivity filter of the KcsA channel in its canonical conducting state, as captured by crystallography, does not allow the diffusion of ions at a rate compatible with experimental data. However, our calculations reveal that the opening of the main gate favors a transient conformational state of the selectivity filter that allows transport rate near the ion diffusion limit. The selectivity filter is thus expected to go from a pre-conducting state with high ion binding affinity to a conducting state with lower ion binding affinity, eventually transiting to the inactivated state. The detailed balance of forces involved in the fine regulation of ion permeation is well described by the latest generation of classical force-fields, which can reveal structural features of ion channels with an unprecedented level of precision.