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

 描述（由申请人提供）：全球氮循环需要将二氮转化为氨，并通过固氮酶在生物学上完成。虽然高度惰性，双氮是“固定”的固氮酶，并使生物可利用，允许吸收形成关键的营养物质，维持生命。固氮酶活性位点的特征在于包含在复杂的氨基酸网络中的多金属核心，这是在还原过程中协调一系列多质子、多电子转移所必需的。虽然对二氮还原至关重要，但这些次级相互作用促进还原的确切分子作用并不为人所知。更确切地说，科学 社区并不精确地知道底物在哪里以及如何结合，以及电子如何传递到N2。因此，在我们对固氮酶反应性的关键贡献者的知识中存在固有的差距。为了解决这一差距，该提案的目标是设计和研究含有高度定向和可变的二级配位球相互作用的小分子构建体。我们将在一级配位范围内保持恒定的环境，并在二级配位范围环境中修饰附加的官能度（氢键供体/受体、刘易斯酸/碱）以评估合作反应性。我们将使用这些中间体结构来测试关键的机制假设，关于使用次级球协同性的底物的分子水平的减少。我们建议，在我们的合成系统，促进固氮酶型活性的相同类型的相互作用进行评估，可以通过扩展，适应描述生物系统。我们获得的知识将提供关键所需的贡献，固氮酶功能的机制研究，也合成固氮酶。高度定向的次级球体相互作用促进的底物活化是许多生物催化循环中的一个广泛主题，因此，我们设想我们的研究结果将具有广泛的实用性，以阐明有意义的贡献酶反应性。

 DESCRIPTION (provided by applicant): 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 during the reduction process. Although crucial for dinitrogen reduction, the precise molecular role that these secondary interactions take to promote reduction is not well known. More explicitly, the scientific community does not precisely know where and how substrates bind, and how electrons are delivered to N2. 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 maintain a constant environment within the primary coordination sphere, and modify appended functionality (hydrogen-bond donors/acceptors, Lewis acids/bases) in the secondary coordination sphere environment to evaluate cooperative reactivity. We will use these intermediate 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.