Mapping of Electron Tunneling Pathways in Proteins

描述(申请人提供)：药物代谢、DNA损伤、呼吸和光合作用都是通过蛋白质间电子传递(ET)反应发生的。蛋白质的三维结构如何控制固定几何构型下的Inmo/ECU/Ar电子转移速率的基本规则现在已经确立。然而，大多数生物ET发生在蛋白质-蛋白质复合体中的一系列几何图形上。这个建议的目的是利用我们对隧穿相互作用的分子控制的理解，以便我们可以建立预测的方法来分析蛋白质间电子转移的ET速率。需要研究的特定蛋白质包括关键的固氮蛋白固氮酶、跨膜呼吸能量转导的细胞色素bc1复合体、氧化还原酶亚硫酸盐氧化酶和细胞色素b5-肌红蛋白氧化还原对。在这些系统中，蛋白质-蛋白质或亚单位-亚单位在一系列几何构型上的对接是电子转移过程的基本要素。我们将把我们建立的ET偶联分析与对接能量学的静电计算结合起来，建立蛋白质间ET反应的定量描述。这些研究将有助于从分子水平上理解与蛋白质铰链运动和蛋白质间复合体形成相关的几何波动如何影响生物医学。例如，朝着我们的基本研究目标取得的进展可能使抗生素的开发能够扰乱线粒体电子转移链中的基本亚单位运动，并可能有助于理解为什么某些点突变会导致新生儿致命的亚硫酸盐氧化酶缺乏症。

DESCRIPTION (provided by applicant): Drug metabolism, DNA damage, respiration, and photosynthesis all occur via interprotein electron-transport (ET) reactions. The basic rules governing how a protein's three-dimensional structure controls intramo/ecu/ar electron transfer rates in fixed geometries is now well established. Most biological ET, however, occurs over a range of geometries in protein-protein complexes. The goal of this proposal is to employ our understanding of the molecular control of tunneling interactions, so that we may establish predictiive methods to analyze ET rates for interprotein electron transfer. Specific proteins to be explored include the key nitrogen fixing protein nitrogenase, the transmembrane energy transducing cytochrome bC1 complex of respiration, the redox enzyme sulfite oxidase, and the cytochrome b5-myoglobin redox couple. In each of these systems, protein-protein or subunit-subunit docking over a range of geometries is an essential element of the electron-transfer process. We will combine our established ET coupling analysis with electrostatic computations of docking energetics to build quantitative descriptions of interprotein ET reactions. These studies will assist in establishing a molecular-level understanding of how geometric fluctuations associated with protein hinge motion and interprotein complex formation may impact biomedicine. For example, progress toward our basic research goal could enable the development of antibiotics that disrupt essential subunit motion in the mitochondrial electron transfer chains and might also assist in establishing an understanding of why certain point mutations lead to fatal sulfite oxidase deficiency in neonatal children.