Elliptical β-barrel deformation underlies gating in VDAC1

Area of Science:

• Biophysics
• Structural Biology
• Membrane Protein Dynamics

Background:

• Voltage-dependent anion channels (VDAC) are crucial for mitochondrial metabolite transport.
• The precise structural mechanism of VDAC gating remains poorly understood.

Purpose of the Study:

• To elucidate the structural mechanism of VDAC gating.
• To investigate the open-to-closed transition of VDAC.

Main Methods:

• Atomistic molecular dynamics (MD) simulations.
• Double electron-electron resonance (DEER) spectroscopy.
• Hydrostatic pressure perturbation.
• Lipid nanodisc reconstitution.

Main Results:

• MD simulations identified intrinsic flexibility in VDAC beta-strands and loops.
• High-pressure DEER confirmed reversible, asymmetric beta-barrel deformation.
• An elliptical VDAC conformation was identified as a pressure-stabilized, gating-competent state.
• Metabolite permeation simulations showed an energy barrier in the elliptical state.

Conclusions:

• VDAC gating is driven by reversible beta-barrel deformation.
• The elliptical conformation represents a transient gating state.
• Pressure-perturbed DEER combined with MD is a powerful strategy for studying transient membrane channel conformations.