title: Structure-guided simulations illuminate the mechanism of ATP transport through VDAC1.
abstract: The voltage-dependent anion channel (VDAC) mediates the flow of metabolites and ions across the outer mitochondrial membrane of all eukaryotic cells. The open channel passes millions of ATP molecules per second, whereas the closed state exhibits no detectable ATP flux. High-resolution structures of VDAC1 revealed a 19-stranded β-barrel with an α-helix partially occupying the central pore. To understand ATP permeation through VDAC, we solved the crystal structure of mouse VDAC1 (mVDAC1) in the presence of ATP, revealing a low-affinity binding site. Guided by these coordinates, we initiated hundreds of molecular dynamics simulations to construct a Markov state model of ATP permeation. These simulations indicate that ATP flows through VDAC through multiple pathways, in agreement with our structural data and experimentally determined physiological rates.
authors.affiliation: 1] Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, Pennsylvania, USA. [2].
authors.forename: Om P
authors.initials: OP
authors.lastname: Choudhary
authors.affiliation: 1] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [2].
authors.forename: Aviv
authors.initials: A
authors.lastname: Paz
authors.affiliation: 1] Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [2].
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Adelman
authors.affiliation: 1] Université Grenoble Alpes, Institut de Biologie Structurale, Grenoble, France. [2] Centre National de la Recherche Scientifique, Institut de Biologie Structurale, Grenoble, France. [3] Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Direction des Sciences du Vivant, Institut de Biologie Structurale, Grenoble, France. [4].
authors.forename: Jacques-Philippe
authors.initials: JP
authors.lastname: Colletier
authors.affiliation: 1] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [2] Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences-Tata Institute of Fundamental Research, Bangalore, India.
authors.forename: Jeff
authors.initials: J
authors.lastname: Abramson
authors.affiliation: 1] Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [2] Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Grabe
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008390:Markov Chains; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
chemical_list: D000255:Adenosine Triphosphate; D050995:Voltage-Dependent Anion Channel 1