title: The electrostatics of VDAC: implications for selectivity and gating.
abstract: The voltage-dependent anion channel (VDAC) is the major pathway mediating the transfer of metabolites and ions across the mitochondrial outer membrane. Two hallmarks of the channel in the open state are high metabolite flux and anion selectivity, while the partially closed state blocks metabolites and is cation selective. Here we report the results from electrostatics calculations carried out on the recently determined high-resolution structure of murine VDAC1 (mVDAC1). Poisson-Boltzmann calculations show that the ion transfer free energy through the channel is favorable for anions, suggesting that mVDAC1 represents the open state. This claim is buttressed by Poisson-Nernst-Planck calculations that predict a high single-channel conductance indicative of the open state and an anion selectivity of 1.75--nearly a twofold selectivity for anions over cations. These calculations were repeated on mutant channels and gave selectivity changes in accord with experimental observations. We were then able to engineer an in silico mutant channel with three point mutations that converted mVDAC1 into a channel with a preference for cations. Finally, we investigated two proposals for how the channel gates between the open and the closed state. Both models involve the movement of the N-terminal helix, but neither motion produced the observed voltage sensitivity, nor did either model result in a cation-selective channel, which is observed experimentally. Thus, we were able to rule out certain models for channel gating, but the true motion has yet to be determined.
authors.affiliation: Carnegie Mellon-University of Pittsburgh Program in Computational Biology, Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Om P
authors.initials: OP
authors.lastname: Choudhary
authors.forename: Rachna
authors.initials: R
authors.lastname: Ujwal
authors.forename: William
authors.initials: W
authors.lastname: Kowallis
authors.forename: Rob
authors.initials: R
authors.lastname: Coalson
authors.forename: Jeff
authors.initials: J
authors.lastname: Abramson
authors.forename: Michael
authors.initials: M
authors.lastname: Grabe
mesh_terms: D000818:Animals; D000838:Anions / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000838:Anions; D002412:Cations; D050505:Mutant Proteins; C494763:Vdac1 protein, mouse; D050995:Voltage-Dependent Anion Channel 1