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

摘要： 全球氮循环需要将二氮转化为氨，这是生物学完成的 固氮酶的作用。虽然高度惰性，双氮是“固定”的固氮酶，并作出 生物可利用性，允许吸收形成维持生命所必需的关键营养素。固氮酶 活性位点的特征在于包含在氨基酸的复杂网络中的多金属核心，这是必需的 以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 过程虽然对二氮还原至关重要，但这些次级相互作用的精确分子作用 用于促进还原作用并不为人所知。更明确地说，科学界并不确切地知道 基质在哪里以及如何结合，电子如何传递，以及产物如何释放。因此，有一个固有的 我们对固氮酶反应性的关键贡献者的知识存在差距。为了弥补这一差距，本提案 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构建体， 协调领域的相互作用。我们将使用合理的设计方法来制备合成类似物， 在仲链中具有可修饰的附加官能团（氢键供体，刘易斯酸/碱 协调球环境，以评估合作反应性。我们将利用这些分子结构 测试关于使用次级球在分子水平上还原底物的关键机理假设 协同性我们建议，在我们的合成系统中评估的相同类型的相互作用， 固氮酶类型的活性可以通过扩展而适于描述生物系统。我们的知识 获得将提供关键需要的贡献，固氮酶功能的机制研究，也是合成 固氮酶由高度定向的次级球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，我们设想我们的研究结果将具有广泛的实用性， 阐明酶反应性的有意义的贡献者。

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.