Science for Life Laboratory and Swedish e-Science Research Center, Department of Applied Physics, KTH Royal Institute of Technology, Solna, Sweden.
Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
Elife. 2021 Oct 15;10:e68369. doi: 10.7554/eLife.68369.
Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating. Consistent with new functional recordings, we report in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed- versus open-like states enabled estimation of open probabilities and transition rates, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs.
配体门控离子通道响应化学刺激传导电流，介导神经元和其他可兴奋细胞的电化学信号转导。对于许多通道，门控的细节仍不清楚，部分原因是结构数据和模拟时间尺度有限。在这里，我们使用增强采样来模拟 pH 门控通道 GLIC，并构建门控的马尔可夫状态模型 (MSM)。与新的功能记录一致，我们在卵母细胞中的分析报告表明，质子化和突变对自由能阱有不同的影响。关闭状态与开放状态的聚类使开放概率和跃迁率的估计成为可能，而更高阶的聚类证实了门控中的构象趋势。此外，我们的模型揭示了状态和质子化依赖性对称化。这表明 MSM 可用于映射离子通道功能状态之间的能量和构象转变，以及它们如何在激活或突变时再现转变，这对建模神经元功能和开发状态选择性药物具有重要意义。
