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Computational investigation of cholesterol binding sites on mitochondrial VDAC

Brian P Weiser1, Reza Salari, Roderic G Eckenhoff

  • 1Department of Anesthesiology and Critical Care and ‡Department of Pharmacology, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania 19104, United States.

The Journal of Physical Chemistry. B
|August 1, 2014
PubMed

Insights

Cholesterol binding to the mitochondrial voltage-dependent anion channel (VDAC) alters protein loop dynamics and stabilizes charged residues. However, cholesterol does not significantly impact ion diffusion through the VDAC channel.

Area of Science:

  • Biophysics
  • Molecular Biology
  • Cellular Respiration

Background:

  • The mitochondrial voltage-dependent anion channel (VDAC) is a key protein in the mitochondrial outer membrane, regulating the passage of ions and metabolites.
  • Cholesterol is known to interact with VDAC in mammalian cells, but the precise effects on human VDAC1 structure and function remain incompletely understood.

Purpose of the Study:

  • To investigate the effects of cholesterol binding on the structure and dynamics of the human VDAC1 protein using atomistic molecular dynamics simulations.
  • To elucidate the specific binding sites and conformational changes induced by cholesterol in VDAC1.

Main Methods:

  • Atomistic molecular dynamics simulations totaling 1.4 microseconds were employed to study human VDAC1.
  • Cholesterol docking was performed at sites identified by NMR, followed by simulations to validate binding modes.
  • A VDAC1 model with cholesterol bound at five unique sites was simulated over multiple 100 ns runs.

Main Results:

  • Cholesterol stably and reproducibly bound to VDAC1 at five specific sites.
  • Bound cholesterol significantly affected the dynamics of loops connecting beta-strands, altering residue fluctuations by 20-30%.
  • Cholesterol binding stabilized charged residues within the channel and localized electrostatic potentials, without significantly affecting ion diffusion.

Conclusions:

  • Cholesterol binding induces modest but specific structural and dynamic changes in human VDAC1, primarily affecting loop regions.
  • The developed VDAC1-cholesterol model provides a valuable tool for future studies on VDAC function under electrochemical forces and interactions with other molecules.

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