title: Voltage Dependence of Conformational Dynamics and Subconducting States of VDAC-1.
abstract: The voltage-dependent anion channel 1 (VDAC-1) is an important protein of the outer mitochondrial membrane that transports energy metabolites and is involved in apoptosis. The available structures of VDAC proteins show a wide β-stranded barrel pore, with its N-terminal α-helix (N-α) bound to its interior. Electrophysiology experiments revealed that voltage, its polarity, and membrane composition modulate VDAC currents. Experiments with VDAC-1 mutants identified amino acids that regulate the gating process. However, the mechanisms for how these factors regulate VDAC-1, and which changes they trigger in the channel, are still unknown. In this study, molecular dynamics simulations and single-channel experiments of VDAC-1 show agreement for the current-voltage relationships of an "open" channel and they also show several subconducting transient states that are more cation selective in the simulations. We observed voltage-dependent asymmetric distortions of the VDAC-1 barrel and the displacement of particular charged amino acids. We constructed conformational models of the protein voltage response and the pore changes that consistently explain the protein conformations observed at opposite voltage polarities, either in phosphatidylethanolamine or phosphatidylcholine membranes. The submicrosecond VDAC-1 voltage response shows intrinsic structural changes that explain the role of key gating amino acids and support some of the current gating hypotheses. These voltage-dependent protein changes include asymmetric barrel distortion, its interaction with the membrane, and significant displacement of N-α amino acids.
authors.affiliation: Computational Biomolecular Dynamics Group, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany. Electronic address: rbrione@gwdg.de.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Briones
authors.affiliation: Institute of Organic and Biomolecular Chemistry, University of Goettingen, Goettingen, Germany.
authors.forename: Conrad
authors.initials: C
authors.lastname: Weichbrodt
authors.affiliation: Department of Chemical and Geological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Paltrinieri
authors.affiliation: Institute of Organic and Biomolecular Chemistry, University of Goettingen, Goettingen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Mey
authors.affiliation: NMR-based Structural Biology, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Villinger
authors.affiliation: NMR-based Structural Biology, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.affiliation: NMR-based Structural Biology, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Lange
authors.affiliation: NMR-based Structural Biology, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany; Department of Neurology, University Medical Center, University of Goettingen, Goettingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: NMR-based Structural Biology, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.affiliation: NMR-based Structural Biology, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Institute of Organic and Biomolecular Chemistry, University of Goettingen, Goettingen, Germany. Electronic address: csteine@gwdg.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Steinem
authors.affiliation: Computational Biomolecular Dynamics Group, Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany. Electronic address: bgroot@gwdg.de.
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002412:Cations / Q000737:chemistry; D004926:Escherichia coli; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008567:Membranes, Artificial; D051379:Mice; D008823:Micelles; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D053835:Unilamellar Liposomes / Q000737:chemistry; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002412:Cations; D008567:Membranes, Artificial; D008823:Micelles; D053835:Unilamellar Liposomes; C494762:VDAC1 protein, human; C494763:Vdac1 protein, mouse; D050995:Voltage-Dependent Anion Channel 1