title: Brownian dynamics simulations of ion transport through the VDAC.
abstract: It is important to gain a physical understanding of ion transport through the voltage-dependent anion channel (VDAC) because this channel provides primary permeation pathways for metabolites and electrolytes between the cytosol and mitochondria. We performed grand canonical Monte Carlo/Brownian dynamics (GCMC/BD) simulations to explore the ion transport properties of human VDAC isoform 1 (hVDAC1; PDB:2K4T) embedded in an implicit membrane. When the MD-derived, space-dependent diffusion constant was used in the GCMC/BD simulations, the current-voltage characteristics and ion number profiles inside the pore showed excellent agreement with those calculated from all-atom molecular-dynamics (MD) simulations, thereby validating the GCMC/BD approach. Of the 20 NMR models of hVDAC1 currently available, the third one (NMR03) best reproduces both experimental single-channel conductance and ion selectivity (i.e., the reversal potential). In addition, detailed analyses of the ion trajectories, one-dimensional multi-ion potential of mean force, and protein charge distribution reveal that electrostatic interactions play an important role in the channel structure and ion transport relationship. Finally, the GCMC/BD simulations of various mutants based on NMR03 show good agreement with experimental ion selectivity. The difference in ion selectivity between the wild-type and the mutants is the result of altered potential of mean force profiles that are dominated by the electrostatic interactions.
authors.affiliation: Center for Bioinformatics, University of Kansas, Lawrence, Kansas; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas.
authors.forename: Kyu Il
authors.initials: KI
authors.lastname: Lee
authors.affiliation: Center for Bioinformatics, University of Kansas, Lawrence, Kansas; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas.
authors.forename: Huan
authors.initials: H
authors.lastname: Rui
authors.affiliation: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Pastor
authors.affiliation: Center for Bioinformatics, University of Kansas, Lawrence, Kansas; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas. Electronic address: wonpil@ku.edu.
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
mesh_terms: D000200:Action Potentials; D004560:Electricity; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport; D007477:Ions; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016062:Porosity; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism*
chemical_list: D007477:Ions; D050505:Mutant Proteins; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1