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  • 标题:Free-energy landscape of ion-channel voltage-sensor–domain activation
  • 本地全文:下载
  • 作者:Lucie Delemotte ; Marina A. Kasimova ; Michael L. Klein
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2015
  • 卷号:112
  • 期号:1
  • 页码:124-129
  • DOI:10.1073/pnas.1416959112
  • 语种:English
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要:SignificanceVoltage-gated cation channels (VGCCs) shape cellular excitability. Their working cycle involves the complex conformational change of modular protein units called voltage sensor domains (VSDs). For over 40 y, these rearrangements have been recorded as "gating" currents, the intensities and kinetics of which are unique signatures of VGCC function. We show that the atomistic description of VSD activation obtained by molecular dynamics simulations and free-energy calculations is consistent with the phenomenological models adopted to account for the macroscopic observables measured by electrophysiology. Our findings pave the way for in silico studies of the VGCC electrophysiological response and hold promise to uncover the molecular underpinnings of inherited channelopathies and modulation of VGCCs by drugs and toxins. Voltage sensor domains (VSDs) are membrane-bound protein modules that confer voltage sensitivity to membrane proteins. VSDs sense changes in the transmembrane voltage and convert the electrical signal into a conformational change called activation. Activation involves a reorganization of the membrane protein charges that is detected experimentally as transient currents. These so-called gating currents have been investigated extensively within the theoretical framework of so-called discrete-state Markov models (DMMs), whereby activation is conceptualized as a series of transitions across a discrete set of states. Historically, the interpretation of DMM transition rates in terms of transition state theory has been instrumental in shaping our view of the activation process, whose free-energy profile is currently envisioned as composed of a few local minima separated by steep barriers. Here we use atomistic level modeling and well-tempered metadynamics to calculate the configurational free energy along a single transition from first principles. We show that this transition is intrinsically multidimensional and described by a rough free-energy landscape. Remarkably, a coarse-grained description of the system, based on the use of the gating charge as reaction coordinate, reveals a smooth profile with a single barrier, consistent with phenomenological models. Our results bridge the gap between microscopic and macroscopic descriptions of activation dynamics and show that choosing the gating charge as reaction coordinate masks the topological complexity of the network of microstates participating in the transition. Importantly, full characterization of the latter is a prerequisite to rationalize modulation of this process by lipids, toxins, drugs, and genetic mutations.
  • 关键词:Kv1.2 ; voltage-gated ion channels ; gating kinetics ; electrophysiology ; metadynamics
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