The Persistent Question of Potassium Channel Permeation Mechanisms.

[Display omitted] • K+ channels are characterized by the highly efficient and selective permeation of K+ ions. • Determining the ion permeation mechanism in K+ channels would explain their remarkable conductive properties. • Many experimental and computational studies have been performed, and multiple ion permeation mechanisms have been proposed - however, the controversies in the field persist and consensus on which mechanism actually occurs is yet to be reached. • In this review, we discuss important milestones in research of ion permeation mechanisms in K+ channels and compare the results obtained with different approaches, as well as present further challenges and possible solutions. Potassium channels play critical roles in many physiological processes, providing a selective permeation route for K+ ions in and out of a cell, by employing a carefully designed selectivity filter, evolutionarily conserved from viruses to mammals. The structure of the selectivity filter was determined at atomic resolution by x-ray crystallography, showing a tight coordination of desolvated K+ ions by the channel. However, the molecular mechanism of K+ ions permeation through potassium channels remains unclear, with structural, functional and computational studies often providing conflicting data and interpretations. In this review, we will present the proposed mechanisms, discuss their origins, and will critically assess them against all available data. General properties shared by all potassium channels are introduced first, followed by the introduction of two main mechanisms of ion permeation: soft and direct knock-on. Then, we will discuss critical computational and experimental studies that shaped the field. We will especially focus on molecular dynamics (MD) simulations, that provided mechanistic and energetic aspects of K+ permeation, but at the same time created long-standing controversies. Further challenges and possible solutions are presented as well. [ABSTRACT FROM AUTHOR]