IDEAS home Printed from https://ideas.repec.org/a/plo/pone00/0045880.html
   My bibliography  Save this article

The Free Energy Barrier for Arginine Gating Charge Translation Is Altered by Mutations in the Voltage Sensor Domain

Author

Listed:
  • Christine S Schwaiger
  • Sara I Börjesson
  • Berk Hess
  • Björn Wallner
  • Fredrik Elinder
  • Erik Lindahl

Abstract

The gating of voltage-gated ion channels is controlled by the arginine-rich S4 helix of the voltage-sensor domain moving in response to an external potential. Recent studies have suggested that S4 moves in three to four steps to open the conducting pore, thus visiting several intermediate conformations during gating. However, the exact conformational changes are not known in detail. For instance, it has been suggested that there is a local rotation in the helix corresponding to short segments of a 3-helix moving along S4 during opening and closing. Here, we have explored the energetics of the transition between the fully open state (based on the X-ray structure) and the first intermediate state towards channel closing (C), modeled from experimental constraints. We show that conformations within 3 Å of the X-ray structure are obtained in simulations starting from the C model, and directly observe the previously suggested sliding 3-helix region in S4. Through systematic free energy calculations, we show that the C state is a stable intermediate conformation and determine free energy profiles for moving between the states without constraints. Mutations indicate several residues in a narrow hydrophobic band in the voltage sensor contribute to the barrier between the open and C states, with F233 in the S2 helix having the largest influence. Substitution for smaller amino acids reduces the transition cost, while introduction of a larger ring increases it, largely confirming experimental activation shift results. There is a systematic correlation between the local aromatic ring rotation, the arginine barrier crossing, and the corresponding relative free energy. In particular, it appears to be more advantageous for the F233 side chain to rotate towards the extracellular side when arginines cross the hydrophobic region.

Suggested Citation

  • Christine S Schwaiger & Sara I Börjesson & Berk Hess & Björn Wallner & Fredrik Elinder & Erik Lindahl, 2012. "The Free Energy Barrier for Arginine Gating Charge Translation Is Altered by Mutations in the Voltage Sensor Domain," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-11, October.
  • Handle: RePEc:plo:pone00:0045880
    DOI: 10.1371/journal.pone.0045880
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045880
    Download Restriction: no

    File URL: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0045880&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pone.0045880?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Stephen B. Long & Xiao Tao & Ernest B. Campbell & Roderick MacKinnon, 2007. "Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment," Nature, Nature, vol. 450(7168), pages 376-382, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Purushotham Selvakumar & Ana I. Fernández-Mariño & Nandish Khanra & Changhao He & Alice J. Paquette & Bing Wang & Ruiqi Huang & Vaughn V. Smider & William J. Rice & Kenton J. Swartz & Joel R. Meyerson, 2022. "Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Franz X. Mittermaier & Thilo Kalbhenn & Ran Xu & Julia Onken & Katharina Faust & Thomas Sauvigny & Ulrich W. Thomale & Angela M. Kaindl & Martin Holtkamp & Sabine Grosser & Pawel Fidzinski & Matthias , 2024. "Membrane potential states gate synaptic consolidation in human neocortical tissue," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Arthur Neuberger & Yury A. Trofimov & Maria V. Yelshanskaya & Jeffrey Khau & Kirill D. Nadezhdin & Lena S. Khosrof & Nikolay A. Krylov & Roman G. Efremov & Alexander I. Sobolevsky, 2023. "Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Arthur Neuberger & Yury A. Trofimov & Maria V. Yelshanskaya & Kirill D. Nadezhdin & Nikolay A. Krylov & Roman G. Efremov & Alexander I. Sobolevsky, 2023. "Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Kota Kasahara & Matsuyuki Shirota & Kengo Kinoshita, 2013. "Ion Concentration-Dependent Ion Conduction Mechanism of a Voltage-Sensitive Potassium Channel," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-8, February.
    6. Mingfeng Zhang & Yuanyue Shan & Duanqing Pei, 2023. "Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Matthew R Skerritt & Donald L Campbell, 2008. "Non-Native R1 Substitution in the S4 Domain Uniquely Alters Kv4.3 Channel Gating," PLOS ONE, Public Library of Science, vol. 3(11), pages 1-7, November.
    8. Arthur Neuberger & Mai Oda & Yury A. Nikolaev & Kirill D. Nadezhdin & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2023. "Human TRPV1 structure and inhibition by the analgesic SB-366791," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    9. Rían W. Manville & J. Alfredo Freites & Richard Sidlow & Douglas J. Tobias & Geoffrey W. Abbott, 2023. "Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Gamma Chi & Qiansheng Liang & Akshay Sridhar & John B. Cowgill & Kasim Sader & Mazdak Radjainia & Pu Qian & Pablo Castro-Hartmann & Shayla Venkaya & Nanki Kaur Singh & Gavin McKinley & Alejandra Ferna, 2022. "Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    11. Willow Coyote-Maestas & David Nedrud & Antonio Suma & Yungui He & Kenneth A. Matreyek & Douglas M. Fowler & Vincenzo Carnevale & Chad L. Myers & Daniel Schmidt, 2021. "Probing ion channel functional architecture and domain recombination compatibility by massively parallel domain insertion profiling," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    12. Rong Shen & Wei Han & Giacomo Fiorin & Shahidul M Islam & Klaus Schulten & Benoît Roux, 2015. "Structural Refinement of Proteins by Restrained Molecular Dynamics Simulations with Non-interacting Molecular Fragments," PLOS Computational Biology, Public Library of Science, vol. 11(10), pages 1-19, October.
    13. Paul J Pfaffinger, 2013. "A Conserved Pre-Block Interaction Motif Regulates Potassium Channel Activation and N-Type Inactivation," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-14, November.
    14. Marcos Matamoros & Xue Wen Ng & Joshua B. Brettmann & David W. Piston & Colin G. Nichols, 2023. "Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pone00:0045880. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosone (email available below). General contact details of provider: https://journals.plos.org/plosone/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.