The persistent question of potassium channel permeation mechanisms

TL;DR

This review critically examines the molecular mechanisms of potassium ion permeation in channels, focusing on structural, computational, and experimental studies, especially the soft and direct knock-on models, highlighting controversies and future challenges.

Contribution

It provides a comprehensive analysis of existing permeation mechanisms, evaluates conflicting data, and discusses the role of molecular dynamics simulations in understanding K+ permeation.

Findings

Identification of two main permeation mechanisms: soft and direct knock-on.

Critical assessment of computational and experimental studies shaping the field.

Discussion of controversies and future challenges in potassium channel permeation research.

Abstract

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.