Mapping of Electron Tunneling Pathways in Proteins

项目摘要 药物代谢，程序性细胞死亡，DNA生物合成和修复，呼吸， 光合作用都通过电子转移（ET）反应机制发生。因此， ET途径是许多人类疾病的潜在原因。由于ET是一种常见的过程， 对于所有形式的生命，病原体中ET途径的分子水平理解可能 也可以用于治疗。我们研究的长期目标是 了解，在分子水平上，生物结构和动力学如何控制关键的速率， ET反应。我们实验室二十多年来的理论进展发现， 结构和动力学决定ET反应机制和速率，我们已经建立了 预测这些比率的有用方法。我们也逐渐了解到，结构化的水可以 在调节电子流中起着重要作用。在上一个补助期，我们发现很长时间- 范围多步电子跳跃在某些厌氧细菌中建立了ET途径。具体 目的是：（1）了解长距离电子耦合的机制 - 在水填充的蛋白质裂缝附近转移到单加氧酶中的底物催化，和 (2)为了了解细菌中微米到厘米距离电荷流动的新机制， 附肢前一种反应对激素的加工至关重要， 神经递质和后者的反应是必不可少的代谢在一些高等真核生物 厌氧细菌在单加氧酶功能的情况下，我们将使用理论方法， 理解ET反应与催化的非常有效的“耦合”的起源，即 在长距离上电子传递与共价键形成的化学过程同步。 在长距离ET沿着细菌电荷转移导管（也称为细菌电荷转移导管）的情况下， 纳米线，我们将采用一种新的理论框架来描述“闪烁共振”运输， 混合的不相干制度的ET，并将评估可行的机制，在这些迷人的 微米到厘米距离的ET反应。我们的目标是建立分子- 生物ET水平预测理论可能会导致新的策略，以解决功能障碍， 电子转移途径，了解氧化应激的起源，并破坏基本的 病原生物的氧化还原链。这里描述的研究将使用 这是统计力学和量子力学方法的结合。我们的标志是 研究一直是我们的理论研究计划与尖端的密切合作， 这一基本战略将持续到下一个研究周期。

Project Summary Drug metabolism, programmed cell death, DNA biosynthesis and repair, respiration, and photosynthesis all occur via electron-transfer (ET) reaction mechanisms. As such, the malfunction of ET pathways is an underlying cause of numerous human diseases. Since ET is a process common to all forms of life, a molecular-level understanding of the ET pathways in pathogenic organisms may be exploited for therapeutic advantage as well. The long-term objective of our research is to understand, at the molecular level, how biological structure and dynamics control the rates of critical ET reactions. Theoretical progress from our laboratory over two decades has found that protein structure and dynamics determine ET reaction mechanisms and rates, and we have established useful methods to predict these rates. We have also come to understand that structured water can play an essential role in mediating electron flow. In the last grant period, we found that very long- range multi-step electron hopping establishes ET pathways in some anaerobic bacteria. The specific aims of this proposal are: (1) to understand the mechanism that couples long-distance electron transfer, in the proximity of a water filled protein cleft, to substrate catalysis in monooxygenases, and (2) to understand a new mechanism for micron to centimeter distance charge flow in bacterial appendages. The former reactions are essential for the processing of hormones and neurotransmitters in higher eukaryotes and the latter reactions are essential for metabolism in some anaerobic bacteria. In the case of monooxygenase function, we will use theoretical methods to understand the origins of the very effective "coupling" of the ET reaction to catalysis, namely the close synchronization of electron delivery over long distances to the chemistry of covalent bond formation. In the case of long distance ET along bacterial charge transfer conduits, also known as bacterial nanowires, we will employ a new theoretical framework to describe "flickering resonant" transport, a mixed incoherent-coherent regime of ET, and will assess viable mechanisms in these fascinating micrometer-to-centimeter distance regime ET reactions. Reaching our aim of establishing molecular- level predictive theories of biological ET could lead to new strategies to address the malfunction of electron transfer pathways, to understand the origins of oxidative stress, and to disrupt the essential redox chains of pathogenic organisms. The research described here will be carried out using a combination of approaches from statistical mechanics and quantum mechanics. The hallmark of our research has been the close collaboration of our theoretical research program with cutting-edge experimental groups, and this essential strategy will continue into the next research cycle.