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、呼吸和光合作用都是通过电子传递（ET）机制发生的。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，这些反应动力学的变化可能导致疾病状态或可用于治疗目的。在蛋白质内ET的情况下，结构和动力学似乎都控制着反应机制。对于蛋白间ET，少数群体构象似乎主导动力学。最近开创性的实验为蛋白质内和蛋白质间ET提供了关键的结构和动力学数据，这应该使我们能够详细了解反应机制。额外的化学修饰和突变研究揭示了反应机制的细节。令人惊讶的速率依赖于蛋白质结构、对接模式和溶剂同位素的报道，而这些观察结果是简单的静态理论模型无法预测的。本提案旨在发展具有现实波动结构的蛋白质内部和蛋白质之间ET的分子水平描述。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种族间水如何控制这一动力学。达到我们的长期目标，即在分子水平上理解蛋白质如何控制ET反应速率，这将使新的策略能够破坏或增强氧化还原过程；这些策略可能导致新的治疗方案源自控制电子沿基本生物电子转移链的流动。

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.