Bioinspired Structure/Function Studies that Leverage Proton-Responsive Secondary Coordination Spheres and Ligand-Based Redox Sites

利用质子响应二级配位球和基于配体的氧化还原位点的仿生结构/功能研究

• 批准号: 9300466
• 负责人: John Gilbertson
• 金额: $ 36.41万
• 依托单位: WESTERN WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300466
• 关键词: Active Sites; Amination; Amines; Amino Acids; Anodes; Area; Binding; Binding Sites; Biological; Biomimetics; Chemicals; Chemistry; Complex; Development; Electrons; Environment; Family; Glare; Halogens; Health; Human; Hydrogen Bonding; Investigation; Ions; Kinetics; Ligands; Metals; Methodology; Modeling; Nitrites; Oxidation-Reduction; Play; Process; Property; Proteins; Protons; Reaction; Regulation; Research; Role; Series; Site; Specific qualifier value; Structure; Structure-Activity Relationship; System; Transition Elements; Translating; base; innovation; metalloenzyme; novel; oxidation; protonation; reaction rate; scaffold; small molecule; synergism; synthetic construct

Project Summary/Abstract The aim of the research described in this proposal is to develop a series of unique and innovative complexes to translate metalloenzyme active site reactivity and selectivity to the realm of synthetic constructs for the study biologically relevant reactions. Many metalloenzymes catalyze reactions that involve either oxidation or reduction of substrate, vital for maintaining human health, and these chemical transformations are generally multi-electron redox processes. The protein environment plays a significant role in the regulation of the reduction potentials to match the specified chemistry of the active site through the use of H-bonding and redox-active amino acids located in the secondary coordination sphere. In other words, the function of health-related metalloenzymes can be understood within the context of changes in the environments proximal to the metal center(s). One glaring weakness of many biomimetic systems is the inability to regulate both the protonation state and the reduction potential of the active site. We plan to overcome these weaknesses by integrating a proton responsive secondary coordination sphere and ligand-based redox-active sites within a single metal- ligand construct. The hypothesis is that by utilizing the redox-active pyridinediimine (PDI) scaffold, it will be possible to unburden the proton-responsivity of the complex from the ligand-based redox-active sites to independently tune both the structural properties of the metal-ligand scaffolds (secondary coordination sphere) and the redox properties (ligand-based redox active sites). We propose that this approach is an effective way to model the reactivity of natural metalloenzymes. Ultimately, the results from this research will lead to a new class of bioinspired complexes that display the elegant control over reactivity that is observed by metalloenzymes. Specific Aims include: (1) Develop a class of bioinspired metal-ligand complexes based on the PDI scaffold that contain proton-responsive secondary coordination spheres. (2) Probe the relationship between the ligand protonation state and the ligand-based redox-active sites. (3) Leverage the proton-responsive secondary coordination sphere and ligand-based redox sites for small molecule activation.

项目总结/摘要 本提案中所述研究的目的是开发一系列独特和创新的复合体， 将金属酶活性位点的反应性和选择性转化到合成结构的领域， 生物相关反应。许多金属酶催化涉及氧化或还原的反应。 减少底物，对维持人类健康至关重要，这些化学转化通常是 多电子氧化还原过程。蛋白质环境在还原的调节中起着重要的作用 通过使用氢键和氧化还原活性， 位于二级配位层的氨基酸。换句话说，与健康相关的功能 金属酶可以在金属附近环境变化的背景下理解， 中心。许多仿生系统的一个明显的弱点是无法调节质子化， 状态和活性位点的还原电位。我们计划通过整合一个 质子响应次级配位球和基于配体的氧化还原活性位点， 配体构建体。假设是通过利用氧化还原活性吡啶二亚胺（PDI）支架， 可以将络合物的质子响应性从基于配体的氧化还原活性位点释放到 独立地调节金属配体支架的结构特性（次级配位球） 和氧化还原性质（基于配体的氧化还原活性位点）。我们认为这种方法是一种有效的方法， 来模拟天然金属酶的反应性。最终，这项研究的结果将导致一个新的 一类生物启发的复合物，显示出对反应性的优雅控制， 金属酶 具体目标包括： (1)开发一类基于PDI支架的生物启发的金属-配体络合物，其包含 质子响应二级配位球。 (2)探讨配体质子化状态与配体基氧化还原活性的关系 网站. (3)利用质子响应二级配位球和基于配体的氧化还原位点， 小分子活化。