Mapping of Electron Tunneling Pathway in Proteins

描述(申请人提供)：药物代谢、细胞程序性死亡、DNA生物合成和修复、呼吸和光合作用都通过电子传递(ET)机制发生。理论和实验进展表明，蛋白质的结构和动力学都控制着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。对于蛋白质间的ET，少数群体构象似乎主导了动力学。最近的开创性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，这些数据应该允许我们对反应机制有一个详细的了解。更多的化学修饰和突变研究正在揭示反应机理的细节。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已被报道，这些观察结果并不是简单的静态理论模型所预期的。这项提议旨在开发具有真实波动结构的蛋白质内部和蛋白质之间的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界面水如何控制这种动力学。实现我们的长期目标，即从分子水平了解蛋白质如何控制ET反应速率，应该能够实现扰乱或增强氧化还原过程的新策略；这些策略可能会导致通过控制基本生物电子转移链上的电子流动来产生新的治疗方案。

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.