Mapping of Electron Tunneling Pathways in Proteins

描述（由申请人提供）：药物代谢、DNA损伤、呼吸和光合作用均通过蛋白质间电子传递（ET）反应发生。蛋白质的三维结构如何控制固定几何结构中的分子内/分子间/分子间电子转移速率的基本规则现在已经很好地建立起来了。然而，大多数生物ET发生在蛋白质-蛋白质复合物的一系列几何形状上。这个建议的目标是利用我们的理解的分子控制的隧道相互作用，使我们可以建立预测的方法来分析ET率的蛋白质间电子转移。待研究的特定蛋白质包括关键的固氮蛋白质固氮酶、呼吸作用的跨膜能量转导细胞色素bC 1复合物、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-蛋白质或亚基-亚基在一系列几何形状上的对接是电子转移过程的基本要素。我们将联合收割机结合我们建立的ET耦合分析与对接能量学的静电计算来建立蛋白质间ET反应的定量描述。这些研究将有助于建立一个分子水平的理解如何几何波动与蛋白质铰链运动和蛋白质间复合物的形成可能会影响生物医学。例如，朝着我们的基础研究目标的进展可以使抗生素的开发，破坏线粒体电子传递链中的必需亚基运动，也可能有助于建立为什么某些点突变导致新生儿致命的亚硫酸氧化酶缺乏症的理解。

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.