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.

项目摘要/摘要 本建议所述研究的目的是开发一系列独特和创新的复合体，以 将金属酶活性部位的反应性和选择性翻译到合成构造物的领域进行研究 与生物相关的反应。许多金属酶催化的反应涉及氧化或 底物的还原，对维持人类健康至关重要，这些化学变化通常是 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作用。 通过使用氢键和氧化还原活性来匹配活性中心的特定化学的电位 氨基酸位于次级配位球体中。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被理解 中心(S)。许多仿生系统的一个明显弱点是无法同时调节质子化和质子化 活性中心的状态和还原潜力。我们计划通过集成一个 单个金属内质子响应性次级配位球和基于配体的氧化还原活性中心- 配基构建。假设通过利用氧化还原活性的吡啶二亚胺(PDI)支架，它将是 可能将络合物的质子响应性从基于配体的氧化还原活性部位卸载到 独立调整金属-配体支架的结构属性(二次配位球) 以及氧化还原性质(基于配体的氧化还原活性中心)。我们认为这种方法是一种有效的方法。 模拟天然金属酶的反应性。最终，这项研究的结果将导致一种新的 一类受生物启发的络合物，展示了对反应性的优雅控制， 金属酶。 具体目标包括： (1)开发了一类基于PDI支架的仿生金属-配体络合物 质子响应的次级配位球体。 (2)探讨了配体质子化状态与配体氧化还原活性的关系 网站。 (3)利用质子响应的二次配位球和基于配体的氧化还原位点 小分子活化。