Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel
Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel
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DOI：
10.1021/ja8033087
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发表时间：
2008-09-24
影响因子：
15
通讯作者：
Chipot, Christophe
中科院分区：
文献类型：
--
作者：
Dehez, Francois;Pebay-Peyroula, Eva;Chipot, Christophe
ADP/ATP载体（AAC）是一种对线粒体的能量供给功能至关重要的膜蛋白，将ADP从膜间隙转运到基质，并以相反的方向转运ATP。基于牛载体的高分辨率2.2埃结构，在真实的膜环境中进行了总共0.53 μ s的经典分子动力学模拟，以破译ADP（3-）跨线粒体内膜易位的早期事件。apo-AAC的检查强调了载体的不可渗透性，阻碍了渗透物向基质的被动运输。从静电势的三维映射照射的静电漏斗形成预期将二磷酸核苷酸快速驱动到内腔底部的特权通道。这一猜想得到了验证，在光的重复，独立的数值实验，其中渗透物是下降的口附近的线粒体载体。ADp（3-）与AAC缝隙的系统结合是其跨内膜运输的早期事件，伴随着复杂的非共价键网络的形成。依赖于使用自适应偏置力的模拟首次揭示了所提出的结合位点对应于描绘载体中ADp（3-）易位的自由能景观的最小值。目前的工作铺平了道路，设计新的核苷酸和新的实验，旨在揭示ADP/ATP跨线粒体膜转运的时序中的关键结构特征。
The ADP/ATP carrier (AAC) is a membrane protein of paramount importance for the energy-fueling function of the mitochondria, transporting ADP from the intermembrane space to the matrix and ATP in the opposite direction. On the basis of the high-resolution, 2.2-angstrom structure of the bovine carrier, a total of 0.53 mu s of classical molecular dynamics simulations were conducted in a realistic membrane environment to decipher the early events of ADP(3-) translocation across the inner membrane of the mitochondria. Examination of apo-AAC underscores the impermeable nature of the carrier, impeding passive transport of permeants toward the matrix. The electrostatic funnel illuminated from three-dimensional mapping of the electrostatic potential forms a privileged passageway anticipated to drive the diphosphate nucleotide rapidly toward the bottom of the internal cavity. This conjecture is verified in the light of repeated, independent numerical experiments, whereby the permeant is dropped near the mouth of the mitochondrial carrier. Systematic association of ADp(3-) to the crevice of the AAC, an early event in its transport across the inner membrane, is accompanied by the formation of an intricate network of noncovalent bonds. Simulations relying on the use of an adaptive biasing force reveal for the first time that the proposed binding site corresponds to a minimum of the free energy landscape delineating the translocation of ADp(3-) in the carrier. The present work paves the way to the design of novel nucleotides and new experiments aimed at unveiling key structural features in the chronology of ADP/ATP transport across the mitochondrial membrane.