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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

基本信息

批准号：
8885996
负责人：
Nathaniel Kolnik Szymczak
金额：
$ 28.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885996
关键词：
Accounting Acids Active Sites Address Air Alkanes Amino Acids Ammonia Binding Biological Carbon Dioxide Carbon monoxide dehydrogenase Chemistry Communities Complex Computer Simulation Coupling Development Electron Transport Electrons Environment Enzymes Ethylenes Goals Heteronuclear NMR Hydrazine Hydrogen Bonding In Situ Individual Knowledge Life Ligands Metals Modification Molecular Nature Nitrogen Nitrogenase Nutrient Oxidases Pathway interactions Play Process Property Protons Reaction Research Research Design Respiration Role Series Site Spectrum Analysis Structure Substrate Interaction System Testing Transition Elements Translating Variant X ray diffraction analysis X-Ray Diffraction analog base biological systems catalyst cytochrome c oxidase enzyme structure expectation metal complex metalloenzyme planetary Atmosphere public health relevance scaffold small molecule synthetic construct uptake

项目摘要

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.