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Conformational dynamics of M2 helices in KirBac channels: helix flexibility in relation to gating via molecular

Alessandro Grottesi1, Carmen Domene, Benjamin Hall

  • 1Department of Biochemistry, University of Oxford, UK.

Biochemistry
|November 3, 2005
PubMed

Insights

Molecular dynamics simulations reveal bacterial potassium channel M2 helices exhibit flexibility. This intrinsic flexibility, centered at a glycine hinge, suggests a gating mechanism coupled to intracellular domain conformational changes.

Area of Science:

  • Biophysics
  • Structural Biology
  • Computational Biology

Background:

  • KirBac1.1 and 3.1 are bacterial homologs of mammalian inward rectifier potassium channels.
  • The M2 helices line the channel pore and form the cytoplasmic hydrophobic gate.

Purpose of the Study:

  • To investigate the conformational dynamics of the KirBac transmembrane domain.
  • To elucidate the role of M2 helix flexibility in potassium channel gating.

Main Methods:

  • Extended molecular dynamics simulations (>20 ns) of KirBac transmembrane domain in lipid bilayer and octane environments.
  • Principal components analysis and eigenvector analysis to study helix motions.
  • Comparison of simulated conformations with X-ray structures of open and closed channels.

Main Results:

  • Simulations revealed bending and swiveling motions of the M2 helices, with a molecular hinge at a conserved glycine residue.
  • A dimer-of-dimers type motion was observed for the M2 helices.
  • The observed flexibility of M2 correlates with conformational differences between closed (undistorted M2) and open (kinked M2) channel structures.

Conclusions:

  • The intrinsic flexibility of the M2 helix, particularly around the glycine hinge, is a key feature of KirBac channels.
  • This flexibility likely contributes to channel gating.
  • A proposed gating model involves M2 helix flexibility coupled to ligand-induced conformational changes in an intracellular 'gatekeeper' domain.

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