Coupled Transfers of Electrons and Protons

描述(由申请人提供)：拟议的研究将对质子耦合电子转移(PCET)过程有一个可获得的、直观的和定量的理解。主要集中在质子和电子在单个动力学步骤中转移到不同的、分离的位置或来自不同的位置的过程。这些多点协同质子-电子转移(MS-CPET)反应在生物学中广泛存在，但还没有被很好地理解。它们是生物能量学的关键，是许多金属酶催化循环的核心，并参与了活性氧物种的化学。MS-CPET在许多药物的代谢和生物激活中起重要作用，MS-CPET过程中的缺陷可导致疾病，例如线粒体电子传输链复合体III的Q循环功能障碍。拟议的研究将检查一系列小分子系统，以开发MS-CPET的基本原理，并模拟特定的生化过程。要考察的体系包括酚类、铁卟啉、Ru络合物，以及铁/硫簇合物的模型。例如，苯酚的研究将揭示酶催化或氧化应激下酪氨酸自由基的形成。使用广泛的模型系统将提供可以自信地转移到更复杂的生物系统的见解。在特定目标1下的研究将建立关于这些过程的直觉，例如，测试我们的假设，即电子和质子的分离通常不会抑制反应速度。E-/H+分离和其他相关参数的系统变化将有助于开发每个参数如何影响MS-CPET反应的定量模型(具体目标2)。这些研究将提供对当前理论的测试，并将探索如何简化这些理论，以捕捉更大的影响，并使实验者更容易理解。具体目标3是发现和了解涉及C-H键的MS-CPET反应的第一个例子，这可能在生化过程中发挥不可估量的作用。总之，不同系统的结果将建立对MS-CPET的新的直观，并将为新的定量模型提供基础。这些将提供对广泛的生物过程的有价值的理解，因此将是建立在生物医学进步基础上的一部分。有关电子转移反应的详细知识已被证明在生物学上具有重要意义。拟议的工作旨在为涉及电子和质子耦合转移的反应建立同样有价值的理解。

DESCRIPTION (provided by applicant): The proposed research will develop an accessible, intuitive, and quantitative under- standing of proton-coupled electron transfer (PCET) processes. The primary focus is on processes in which a proton and an electron transfer in a single kinetic step but go to or come from distinct, separated sites. These multiple-site concerted proton-electron transfer (MS-CPET) reactions are widespread across biology but are not well understood. They are key to bioenergetics, central to the catalytic cycles of numerous metalloenzymes, and are involved in the chemistry of reactive oxygen species. MS-CPET is important in metabolism and bioactivation of many drugs, and defects in MS-CPET processes can lead to disease, for instance malfunctioning of the Q-cycle in complex III of the electron transport chain in mitochondria. The proposed studies will examine a range of small molecule systems to develop the fundamentals of MS-CPET and to model specific biochemical processes. The systems to be examined include phenols, iron porphyrins, ruthenium complexes, and models for iron/sulfur cluster cofactors. The phenol studies, for instance, will shed light on the formation of tyrosyl radicals in enzymatic catalysis or under oxidative stress. Using a broad range of model systems will provide insights that can be confidently transferred to more complex biological systems. Studies under specific aim 1 will build an intuition about these processes, for instance testing our hypothesis that separation of the electron and proton often does not inhibit the rate of reaction. Systematic variation of the e-/H+ separation and other relevant parameters will help develop quantitative models of how each parameter affects the MS-CPET reactions (specific aim 2). These studies will provide tests of current theory, and will explore how to simplify these theories to capture the larger effects and to be more accessible to experimentalists. Specific aim 3 is to discover and understand the first examples of MS-CPET reactions involving C-H bonds, which could play an unappreciated role in biochemical processes. Together, the results from the different systems will build new intuition about MS-CPET and will provide the basis for new quantitative models. These will provide valuable understanding of a wide range of biological processes, and thus will be part of the foundation on which biomedical advances are built. The detailed knowledge available for electron transfer reactions has proven to be of great importance in biology. The work proposed aims to build a similarly valuable understanding for reactions that involve coupled transfers of electrons and protons.