结构导向模拟阐明了 ATP 通过 VDAC1 运输的机制。
Structure-guided simulations illuminate the mechanism of ATP transport through VDAC1.
机构信息
1] Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, Pennsylvania, USA. [2].
1] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [2].
出版信息
Nat Struct Mol Biol. 2014 Jul;21(7):626-32. doi: 10.1038/nsmb.2841. Epub 2014 Jun 8.
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.
摘要
电压依赖性阴离子通道 (VDAC) 介导所有真核细胞线粒体外膜的代谢物和离子流动。开放通道每秒通过数百万个 ATP 分子，而关闭状态则没有可检测到的 ATP 通量。VDAC1 的高分辨率结构显示出一个 19 股 β-桶，其中一个 α-螺旋部分占据中央孔道。为了了解 ATP 通过 VDAC 的渗透，我们在存在 ATP 的情况下解析了小鼠 VDAC1 (mVDAC1) 的晶体结构，揭示了一个低亲和力结合位点。根据这些坐标，我们启动了数百个分子动力学模拟，构建了 ATP 渗透的马尔可夫状态模型。这些模拟表明，ATP 通过 VDAC 以多种途径流动，与我们的结构数据和实验确定的生理速率一致。
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