The Role of Secondary Interactions Relevant to Biological Reductions of Small Molecules

摘要： 氮素转化为氨是全球氮循环所必需的，它是通过生物方式完成的。 通过固氮酶。虽然高度惰性，但氮素被固氮酶“固定”，并使 生物可利用的，允许吸收形成维持生命所需的关键营养物质。固氮酶 活性中心具有一个包含在复杂的氨基酸网络中的多金属核心，这是必需的 在还原过程中协调一系列多质子、多电子转移到小分子底物 进程。尽管对氮的还原至关重要，但这些次级相互作用所起的确切分子作用 起到促进减量的作用还不为人所知。更明确地说，科学界并不确切地知道 底物在哪里结合以及如何结合，电子是如何传递的，以及产品是如何释放的。因此，有一种内在的 我们对固氮酶活性的关键贡献者的认识存在差距。为了解决这一差距，这项提议 目标是设计和研究含有高度定向和可变二级结构的小分子结构 配位球相互作用。我们将使用合理的设计方法来准备合成类似物 特征可修改的附加官能团(氢键供体、Lewis酸/碱) 评价协同反应性的配位球环境。我们将利用这些分子结构 利用二次球测试关于底物分子水平还原的关键机械假说 协作性。我们认为，在我们的合成系统中评估的相同类型的交互作用促进了 通过引申，固氮酶类型的活性可以适用于描述生物系统。我们所了解的知识 Acquire将为固氮酶功能的机制研究和合成提供所需的关键贡献 固氮酶。由高度定向的次级球体相互作用促进的底物活化是一个广泛的主题 在许多生物催化循环中，因此，我们预计我们的研究结果将对 阐明对酶反应有意义的贡献者。

Abstract: The conversion of dinitrogen to ammonia is required for the global nitrogen cycle and is accomplished biologically by nitrogenase enzymes. Although highly inert, dinitrogen is “fixed” by nitrogenase enzymes, and made biologically available, allowing uptake to form key nutrients necessary to sustain life. The nitrogenase enzyme active site features a multi-metallic core contained within a complex network of amino acids, which are necessary to orchestrate a series of multi-proton, multi-electron transfers to small molecule substrates during the reduction process. Although crucial for dinitrogen reduction, the precise molecular role that these secondary interactions serve to promote reduction is not well known. More explicitly, the scientific community does not precisely know where and how substrates bind, how electrons are delivered, and products released. Thus, there is an inherent gap in our knowledge underlying key contributors to nitrogenase reactivity. To address this gap, this proposal targets the design and study of small molecular constructs that contain highly directed and variable secondary coordination sphere interactions. We will use a rational design approach to prepare synthetic analogues that feature modifiable appended functionality (hydrogen-bond donors, Lewis acids/bases) in the secondary coordination sphere environment to evaluate cooperative reactivity. We will use these molecular structures to test key mechanistic hypotheses regarding the molecular-level reduction of substrates using secondary-sphere cooperativity. We propose that the same type of interactions evaluated in our synthetic systems that promote nitrogenase-type activity can be, by extension, adapted to describe biological systems. The knowledge we acquire will provide key needed contributions to mechanistic studies of nitrogenase function and also synthetic nitrogenases. Substrate activation promoted by highly directed secondary sphere interactions is a broad theme among many biocatalytic cycles, and thus, we envision that the results of our studies will have broad utility to elucidate meaningful contributors to enzymatic reactivity.