The Electrostatics of VDAC: Implications for Selectivity and Gating

被引:77
作者
Choudhary, Om P. [5 ]
Ujwal, Rachna [4 ]
Kowallis, William [3 ]
Coalson, Rob [3 ]
Abramson, Jeff [4 ]
Grabe, Michael [1 ,2 ]
机构
[1] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Sch Med, Dept Computat Biol, Pittsburgh, PA 15260 USA
[3] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA
[5] Univ Pittsburgh, Program Computat Biol, Carnegie Mellon Univ, Pittsburgh, PA 15260 USA
基金
美国国家科学基金会;
关键词
VDAC; ion channel; continuum electrostatics; gating charge; PNP; MITOCHONDRIAL OUTER-MEMBRANE; DEPENDENT ANION CHANNEL; PEPTIDE-SPECIFIC ANTIBODIES; SHAKER POTASSIUM CHANNELS; ION CHANNELS; K+ CHANNEL; ELECTRODIFFUSION THEORY; MOLECULAR-DYNAMICS; BROWNIAN DYNAMICS; NEUROSPORA-CRASSA;
D O I
10.1016/j.jmb.2009.12.006
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:580 / 592
页数:13
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