Liu Haoran, Biedermann Johann, Sun Han
Research Unit of Structural Chemistry & Computational Biophysics, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
Department of Chemistry, Technische Universität Berlin, Berlin, Germany.
Commun Biol. 2025 Aug 23;8(1):1272. doi: 10.1038/s42003-025-08705-5.
Mammalian cyclic nucleotide-gated (CNG) ion channels play a fundamental role in signal transduction within the visual and olfactory sensory cells, converting external stimuli into electrical signals. Here, using large-scale atomistic molecular dynamics (MD) simulations of three different constructs under applied transmembrane voltages, we uncover the atomistic mechanism of monovalent cation permeation in the homotetrameric CNGA1 channel. Owing to the high plasticity and large dimensions of its selectivity filter (SF), monovalent cation binding within the SF of the CNGA1 channel is more dynamic and diffuse compared to that in potassium-selective and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. K and Na permeation in CNGA1 involves hydrated cations passing through the SF with strong occupancy at three regions. In addition, we proposed that the higher Na occupancy in the SF compare to K underlies the experimentally observed larger Na conductance. Our study provides atomistic insights into non-selective cation permeation mechanisms that are not accessible through static structural analysis alone.
哺乳动物环核苷酸门控（CNG）离子通道在视觉和嗅觉感觉细胞的信号转导中起着基础性作用，将外部刺激转化为电信号。在此，我们通过对三种不同构建体在施加跨膜电压下进行大规模原子分子动力学（MD）模拟，揭示了同四聚体CNGA1通道中单价阳离子渗透的原子机制。由于其选择性过滤器（SF）具有高可塑性和大尺寸，与钾选择性通道和超极化激活的环核苷酸门控（HCN）通道相比，CNGA1通道SF内的单价阳离子结合更具动态性和扩散性。CNGA1中的钾和钠渗透涉及水合阳离子通过SF，在三个区域有很强的占据。此外，我们提出，与钾相比，SF中钠的占据率更高是实验观察到的钠电导更大的基础。我们的研究为非选择性阳离子渗透机制提供了原子层面的见解，而这些机制仅通过静态结构分析是无法获得的。
