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

与小分子生物还原相关的次级相互作用的作用

• 批准号: 10451600
• 负责人: Nathaniel Kolnik Szymczak
• 金额: $ 37.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451600
• 关键词: Acids; Active Sites; Address; Amino Acids; Ammonia; Atmosphere; Binding; Biological; Biological Availability; Communities; Complex; Development; Electron Transport; Electrons; Environment; Enzymes; Hydrogen Bonding; Knowledge; Life; Molecular; Molecular Structure; Nitrogen; Nitrogenase; Nutrient; Process; Protons; Role; Series; System; Testing; Translating; analog; base; biological systems; catalyst; design; metallicity; public health relevance; rational design; small molecule; uptake

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.

抽象的： 全球氮循环需要二氮转化为氨，并在生物学上完成 尽管高度惰性，但通过氮酶，二氮是由氮酶“固定”的，并制成 生物学上可用，使摄取能够构成维持生命所需的关键营养。氮酶 活动位点具有一个多金属核心，该核心包含在复杂的氨基酸网络中，这是必要的 策划一系列多元原子，多电子转移到还原过程中向小分子底物转移 process。尽管对减少二氮的至关重要，但这些次级相互作用的精确分子作用 促进减少的服务并不是众所周知。更明确地，科学界并不确切知道 底物的限制，电子的传递方式以及释放产品。那有一个继承 我们的知识差距是氮酶反应性的主要因素。为了解决这个差距，该提议 针对包含高度定向和可变次级的小分子构建体的设计和研究 协调球相互作用。我们将使用一种理性的设计方法来准备合成类似物 特征可修改的附加功能（氢键供体，刘易斯酸/碱） 协调领域环境评估合作反应性。我们将使用这些分子结构 测试有关使用次级球的底物降低分子级降低的关键机械假设 合作。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以促进 氮酶类型的活性可以扩展为描述生物系统。我们的知识 获取将为氮酶功能的机理研究提供关键的贡献以及合成 氮酶。由高度定向的次级球相互作用促进的底物激活是一个广泛的主题 在许多生物催化循环中，我们认为我们的研究结果将具有广泛的实用性 阐明有意义的酶反应性贡献者。