Ion Conduction Mechanism as a Fingerprint of Potassium Channels

Abstract

K+-channels are membrane proteins that regulate the selective conduction of potassium ions across cell membranes. Although the atomic mechanisms of K+ permeation have been extensively investigated, previous work focused on characterizing the selectivity and occupancy of the binding sites, the role of water molecules in the conduction process, or the identification of the minimum energy pathways enabling permeation. Here, we exploit molecular dynamics simulations and the analytical power of Markov state models to perform a comparative study of ion conduction in three distinct channel models. Significant differences emerged in terms of permeation mechanisms and binding site occupancy by potassium ions and/or water molecules from 100 μs cumulative trajectories. We found that, at odds with the current paradigm, each system displays a characteristic permeation mechanism, and thus, there is not a unique way by which potassium ions move through K+-channels. The high functional diversity of K+-channels can be attributed in part to the differences in conduction features that have emerged from this work. This study provides crucial information and further inspiration for wet-lab chemists designing new synthetic strategies to produce versatile artificial ion channels that emulate membrane transport for their applications in diagnosis, sensors, the next generation of water treatment technologies, etc., as the ability of synthetic channels to transport molecular ions across a bilayer in a controlled way is usually governed through the choice of metal ions, their oxidation states, or their coordination geometries.

A Multi-Scale Approach to Model K+ Permeation Through the KcsA Channel

“…This will allow to evaluate the soundness of a postulated permeation process derived from structural data and MD results. One such model has been recently found using long MD simulations, where K + permeation through the KcsA channel can be described by a quite simple sequence of Markov states ( Domene et al, 2021 ). In this type of model, which we may define as an association/dissociation model (A/D model, ( Nelson, 2011 )), the current is produced by the binding of a K + ion to the SF on one side of the membrane and the unbinding of another K + ion on the other side.…”

Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights From Experimental and Molecular Dynamics Simulations Studies

“…Similar method had been successfully used by other research groups. (Richter et al, 2017;Domene et al, 2021) The peptide was modelled using the AMBER14sb force field, and the lipid molecules were modelled using the AMBER lipid17 force field. Initially, the peptide, modelled in a helical conformation, was placed 4 nm above the membrane center, followed by solvation with water molecules using the TIP3 model of each system.…”

Unifying Single-Channel Permeability From Rare-Event Sampling and Steady-State Flux

“…Herein, we show that a slightly modified ISD equation yields a single-channel permeability consistent with a mean first passage time (MFPT) based method, which extracts detailed kinetics along the molecular permeation pathway directly from rare-event sampling methods. Recent examples of such rare-event sampling applied on ion channels include milestoning ( Alberini et al, 2018 ; Cottone et al, 2020 ; Jiang et al, 2021a ), weighted ensemble sampling ( Adelman and Grabe, 2015 ), and Markov state models ( Teo and Schulten, 2013 ; Choudhary et al, 2014 ; Domene et al, 2021 ; Hempel et al, 2021 ). In theory, the PMF-based method, MFPT-based method, and steady-state flux under voltage should converge to the same single-channel permeability for the same studied system.…”