Mapping of Electron Tunneling Pathway in Proteins

描述（由申请人提供）：药物代谢、程序性细胞死亡、DMA生物合成和修复、呼吸和光合作用均通过电子传递（ET）机制发生。理论和实验进展表明，蛋白质结构和动力学控制ET反应动力学，这些反应的动力学变化可能导致疾病状态或可用于治疗目的。在蛋白质内的ET的情况下，结构和动力学似乎都控制反应机制。对于蛋白质间ET，少数群体构象似乎占主导地位的动力学。种子最近的实验提供了关键的结构和动力学数据的蛋白质内和蛋白质间的ET，应该让我们发展一个详细的了解的反应机制。其他化学修饰和突变研究正在揭示反应机制的细节。已经报道了令人惊讶的速率对蛋白质结构、对接模式和溶剂同位素的依赖性，而这些观察结果是简单的静态理论模型无法预料的。该提案旨在开发具有现实波动结构的蛋白质内和蛋白质之间的ET分子水平描述。这些研究将针对蛋白质和溶剂动力学对蛋白质内和蛋白质间ET动力学的影响，目的是建立规则来定义蛋白质结构和界面水如何控制这种动力学。达到我们的长期目标，发展一个分子水平的理解蛋白质如何控制ET反应速率应使新的策略，以破坏或增强氧化还原过程，这些策略可能会导致新的治疗方案，从控制电子流沿着基本的生物电子转移链。

DESCRIPTION (provided by applicant): Drug metabolism, programmed cell death, DMA biosynthesis and repair, respiration, and photosynthesis all occur via electron-transport (ET) mechanisms. Theoretical and experimental advances indicate that both protein structure and dynamics control ET reaction kinetics, and that changes in the kinetics of these reactions may lead to disease states or may be used for therapeutic purposes. In the case of ET within proteins, structure and dynamics both appear to control the reaction mechanism. For inter-protein ET, minority population conformations appear to dominate the kinetics. Seminal recent experiments provide key structural and kinetic data for intra-protein and inter-protein ET that should allow us to develop a detailed understanding of the reaction mechanisms. Additional chemical modification and mutation studies are revealing details of the reaction mechanisms. Surprising rate dependencies on protein structure, docking mode, and solvent isotopes have been reported, and these observations are not anticipated by the simple static theoretical models. This proposal aims to develop molecular-level descriptions of ET within and between proteins with realistic fluctuating structures. The studies will target the influence of protein and solvent dynamics on intra-protein and inter-protein ET kinetics, with the aim of establishing rules to define how protein structure and interracial water control this kinetics. Reaching our long-term goal of developing a molecular-level understanding of how proteins control ET reaction rates should enable new strategies to disrupt or enhance redox processes; these strategies could lead to new therapeutic schemes derived from controlling the flow of electrons along essential biological electron transfer chains.