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

 说明(申请人提供)：氮素转化为氨是全球氮循环所必需的，由固氮酶在生物学上完成。虽然高度惰性，但氮素是由固氮酶固定的，并在生物上可用，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，这些氨基酸是在还原过程中协调一系列多质子、多电子转移所必需的。虽然对氮素还原至关重要，但这些次级相互作用促进还原的确切分子作用尚不为人所知。更明确地说，科学的 社区并不确切地知道底物在哪里以及如何结合，以及电子是如何传递到氮气的。因此，我们对固氮酶活性的关键因素的了解存在着内在的差距。为了解决这一差距，该建议的目标是设计和研究包含高度定向和可变的二级配位球相互作用的小分子结构。我们将在初级配位圈内保持恒定的环境，并在次级配位圈环境中修改附加官能团(氢键供体/受体，Lewis酸/碱)以评估合作反应性。我们将使用这些中间结构来测试有关使用次级球协作性的底物分子水平还原的关键机械假设。我们建议，在我们的合成系统中评估的促进固氮酶类型活性的相同类型的相互作用可以推广到描述生物系统。我们所获得的知识将为固氮酶功能的机制研究以及合成固氮酶提供关键的必要贡献。在许多生物催化循环中，由高度定向的二级球相互作用促进的底物激活是一个广泛的主题，因此，我们的研究结果将对阐明对酶反应有意义的贡献者具有广泛的实用价值。

 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.