Mapping of Electron Tunneling Pathways in Proteins

描述（由申请人提供）：药物代谢、程序性细胞死亡、DNA生物合成和修复、呼吸和光合作用均通过电子转移（ET）反应机制发生。因此，ET途径的功能障碍是许多人类疾病的根本原因。由于ET是所有生命形式共同的过程，因此对病原生物体中ET途径的分子水平理解也可用于治疗优势。我们研究的长期目标是在分子水平上了解生物结构和动力学如何控制关键ET反应的速率。我们实验室二十多年来的理论进展发现，蛋白质结构和动力学决定了ET反应机制和速率，我们已经建立了预测这些速率的有用方法。我们也逐渐了解到，结构水可以在介导电子流动中发挥重要作用。在上一个资助期，我们发现在一些厌氧细菌中，非常长距离的多步电子跳跃建立了ET途径。这个提议的具体目的是：（1）了解在充满水的蛋白质裂缝附近的长距离电子转移与单加氧酶中的底物催化的耦合机制，以及（2）了解细菌附件中微米至厘米距离电荷流动的新机制。前一种反应是高等真核生物中激素和神经递质加工所必需的，后一种反应是某些厌氧细菌中代谢所必需的。在单加氧酶功能的情况下，我们将使用理论方法来理解非常有效的“耦合”的ET反应的催化，即电子传递的密切同步的化学共价键形成的起源。在长距离ET沿着细菌电荷转移管道，也被称为细菌纳米线的情况下，我们将采用一种新的理论框架来描述“闪烁共振”运输，ET的混合非相干制度，并将评估这些迷人的微米到厘米的距离制度ET反应的可行机制。达到我们建立生物ET的分子水平预测理论的目标可能会导致新的策略来解决电子传递途径的故障，了解氧化应激的起源，并破坏病原生物体的基本氧化还原链。这里描述的研究将使用统计力学和量子力学的方法相结合进行。我们研究的标志是我们的理论研究计划与尖端实验小组的密切合作，这一重要战略将持续到下一个研究周期。

DESCRIPTION (provided by applicant): 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 catalysi 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.