Molecular dynamics study of Cl− permeation through cystic fibrosis transmembrane conductance regulator (CFTR)

作者：Zhiwei Zeng, Paul Linsdell, Régis Pomès · 发表于：Cellular and Molecular Life Sciences · 年份：2023 · DOI：10.1007/s00018-022-04621-7 · 被引用次数：20 · 研究领域：Cystic Fibrosis Research Advances、Advanced biosensing and bioanalysis techniques、Legume Nitrogen Fixing Symbiosis

Abstract The recent elucidation of atomistic structures of Cl − channel CFTR provides opportunities for understanding the molecular basis of cystic fibrosis. Despite having been activated through phosphorylation and provided with ATP ligands, several near-atomistic cryo-EM structures of CFTR are in a closed state, as inferred from the lack of a continuous passage through a hydrophobic bottleneck region located in the extracellular portion of the pore. Here, we present repeated, microsecond-long molecular dynamics simulations of human CFTR solvated in a lipid bilayer and aqueous NaCl. At equilibrium, Cl − ions enter the channel through a lateral intracellular portal and bind to two distinct cationic sites inside the channel pore but do not traverse the narrow, de-wetted bottleneck. Simulations conducted in the presence of a strong hyperpolarizing electric field led to spontaneous Cl − translocation events through the bottleneck region of the channel, suggesting that the protein relaxed to a functionally open state. Conformational changes of small magnitude involving transmembrane helices 1 and 6 preceded ion permeation through diverging exit routes at the extracellular end of the pore. The pore bottleneck undergoes wetting prior to Cl − translocation, suggesting that it acts as a hydrophobic gate. Although permeating Cl − ions remain mostly hydrated, partial dehydration occurs at the binding sites and in the bottleneck. The observed Cl − pathway is largely consistent with the ...