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Related Experiment Videos

Interface connections of a transmembrane voltage sensor.

J Alfredo Freites1, Douglas J Tobias, Gunnar von Heijne

  • 1Department of Physiology and Biophysics and Program in Macromolecular Structure, University of California, Irvine, CA 92697-4560, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 12, 2005
PubMed
Summary

Molecular dynamics simulations show that water and lipid phosphates stabilize voltage-sensitive ion channel S4 helices. This interaction allows charged residues to cross the lipid bilayer, challenging previous energetic models.

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Area of Science:

  • Biophysics
  • Structural Biology
  • Computational Biology

Background:

  • Voltage-sensitive ion channels regulate cellular excitability via transmembrane potential changes.
  • S4 segments, rich in positive charges (arginine), act as voltage sensors, moving in response to electrical fields.
  • The paddle model suggests S4 movement within the lipid bilayer, yet direct charge exposure to lipids was considered energetically unfavorable.

Purpose of the Study:

  • To investigate the energetics of S4 helix insertion into a lipid bilayer.
  • To reconcile experimental findings of S4 helix membrane insertion with classical biophysical models.
  • To elucidate the molecular mechanisms stabilizing charged S4 helices within the membrane environment.

Main Methods:

  • Molecular dynamics (MD) simulations of an isolated transmembrane S4 helix.

Related Experiment Videos

  • Analysis of interactions between the S4 helix, lipid phosphates, and water molecules.
  • Calculation of the effective dielectric thickness of the lipid bilayer around the S4 helix.

    • Main Results:

    • A stabilizing hydrogen-bonded network forms between arginine residues of the S4 helix, water, and lipid phosphates.
    • This network effectively reduces the hydrophobic barrier, allowing the charged helix to span the membrane.
    • The simulation indicated a local reduction of the bilayer hydrocarbon core thickness to approximately 10 Å.

    Conclusions:

    • The lipid bilayer can adapt locally to accommodate strongly perturbing protein structures like S4 helices.
    • Phospholipids can act as a structural extension of the protein, facilitating the movement of charged voltage sensors.
    • This finding challenges classical energetic barriers for charged residue exposure within lipid bilayers.