Computational methods for unlocking the secrets of potassium channels: Structure, mechanism, and drug design

Abstract

Potassium (K+) channels play vital roles in various physiological functions, including regulating K+ flow in cell membranes, impacting nervous system signal transduction, neuronal firing, muscle contraction, neurotransmitters, and enzyme secretion. Their activation and switch‐off are directly linked to diseases like arrhythmias, atrial fibrillation, and pain etc. Although the experimental methods play important roles in the studying the structure and function of K+ channels, they are still some limitations to enclose the dynamic molecular processes and the corresponding mechanisms of conformational changes during ion transport, permeation, and gating control. Relatively, computational methods have obvious advantages in studying such problems compared with experimental methods. Recently, more and more three‐dimensional structures of K+ channels have been disclosed based on experimental methods and in silico prediction methods, which provide a good chance to study the molecular mechanism of conformational changes related to the functional regulations of K+ channels. Based on these structural details, molecular dynamics simulations together with related methods such as enhanced sampling and free energy calculations, have been widely used to reveal the conformational dynamics, ion conductance, ion channel gating, and ligand binding mechanisms. Additionally, the accessibility of structures also provides a large space for structure‐based drug design. This review mainly addresses the recent progress of computational methods in the structure, mechanism, and drug design of K+ channels. After summarizing the progress in these fields, we also give our opinion on the future direction in the area of K+ channel research combined with the cutting edge of computational methods.This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Structure and Mechanism > Computational Biochemistry and Biophysics Data Science > Chemoinformatics

Conserved A-to-I RNA editing with non-conserved recoding expands the candidates of functional editing sites

“…Editing site was pinpointed in the plot. The subunits (including S1~S6 and a linker region) were labeled according to reference [ 45 ]. (c) Domain structures of Drosophila CG16974.…”

“…The pre-editing and post-edited structures were adjusted to the same angle ( Figure 5b ). According to a recent comprehensive review [ 45 ], the ion transport domain of Shab consists of seven main helixes including S1–S6 and a linker. S1–S3 are the sensor domain, and S4–S6 are the pore-forming domain.…”

“…S1–S3 are the sensor domain, and S4–S6 are the pore-forming domain. The movement and conformational change of S4 helix directly controls the membrane potential and channel activity, where the distance between S4 and the sensor domain is a crucial determinant [ 45 ]. Interestingly, the Drosophila Thr>Ala recoding site is located in S4 ( Figure 5b ).…”