Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel

eLife

Cathrine Bergh¹  Erik Lindahl²  Stephanie A Heusser³  Rebecca Howard³ 

[1] 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 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;Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden;

关键词: ligand-gated ion channel;    gating;    allosteric modulation;    molecular dynamics;    electrophysiology;    markov state model;    Xenopus;   

DOI  :  10.7554/eLife.68369

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY