Modeling Modern Concepts in Metalloenzyme Active Site Reactivity

金属酶活性位点反应性的现代概念建模

• 批准号: 10623574
• 负责人: Neil Carleton Tomson
• 金额: $ 38.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623574
• 关键词: Active Sites; Binding; Binding Sites; Biology; Biomimetics; Biotechnology; Chemistry; Complex; Copper; Coupled; Data; Development; Disease; Electron Transport; Electrostatics; Enzymatic Biochemistry; Enzymes; Genetic; Geometry; Goals; Heme; Investigation; Ions; Knowledge; Laboratories; Ligands; Lipoxygenase; Location; Metabolism; Metals; Mission; Modeling; Modernization; Molecular; Mononuclear; Nitrogenase; Nuclear; Pathway interactions; Play; Positioning Attribute; Process; Proteins; Protons; Public Health; Research; Roentgen Rays; Role; Site; Spectrum Analysis; Structure; System; Transition Elements; United States National Institutes of Health; Work; absorption; catalyst; computer studies; density; electric field; electronic structure; expectation; improved; inhibitor; insight; metal complex; metalloenzyme; novel drug class; novel strategies; photosystem II; programs; sample fixation; small molecule; theories; trend

Project Summary The overarching goal of this chemistry is to develop new avenues in biomimetic transition metal chemistry as a way of modelling metalloenzyme active sites. This work is divided into two sections. The first aims to evaluate the ability of strong, local electrostatic fields in the secondary coordination sphere of a metal center to impact the metal’s electronic structure and reactivity profile. Electrostatic fields play critical roles in enzymology, and recent computational studies have provided the first indication that they operate at metalloenzymes. Lipoxygenases, blue copper proteins, photosystem II, and both heme and non-heme Fe centers have been variously predicted to use local electrostatic fields to facilitate electron transfer, proton transfer, or proton-coupled electron transfer (PCET). Preliminary results from our laboratory have mimicked the ability of enzymes to organize electric fields in a way that is advantageous to the active site’s chemistry. This electrostatic preorganization in our molecular compounds was then shown to regulate both O2 binding to CuI ions and the rates of subsequent intermolecular PCET chemistry. The proposed research will first delineate the extent to which electrostatic fields are able to gate PCET – a process of fundamental importance to metabolism. Unexpected trends in the preliminary data hint at interesting electrostatic field effects that will need to be investigated in a systematic fashion. Next, the use of secondary coordination sphere electrostatic effects will be explored for their ability to stabilize key intermediates that have been proposed to develop during O2 processing at various monocopper sites in biology. Electrostatic effects are expected to provide a useful shift in the energy landscape for stabilizing these species. Lastly, a new approach will be developed for identifying secondary coordination sphere electrostatic effects with X-ray absorption spectroscopy and density functional theory, based on the expectation that oriented electrostatic fields will tune the energies and intensities of XAS acceptor states. The broad scope of this section of the research program is intended to improve our ability to identify, tune, and use electrostatic fields in molecular transition metal systems, as is needed for creating effective biomimetics. In the second section of this research program, we will investigate the ability of constrained geometry cluster compounds to effect biologically relevant N2 fixation chemistry. Many metalloenzymes use multinuclear active sites for small molecule activation, but efforts to mimic their structures and catalytic activities have lagged, with most relying on mononuclear transition metal complexes. Recent developments in the study of the nitrogenase enzymes have identified constrained geometry dinuclear sites as the likely locations for N2 fixation. In preliminary investigations, we have made use of a ligand system that is able to constrain the positions of two metal centers housed within a macrocyclic framework. The diiron version of this complex has been shown to form a number of species that are relevant to mechanisms that have been put forward for N2 fixation at the nitrogenase enzymes. The proposed work will perform a step-by-step investigation into the ability of constrained geometry diiron sites to shuttle nitrogenous substrates along an N2 reduction pathway. Together, these two sections are expected to advance our understanding of ways in which metalloenzymes perform some of the most challenging transformations in biology.

项目摘要 这种化学的首要目标是开发仿生过渡金属化学的新途径， 模拟金属酶活性位点的方法。这项工作分为两个部分。第一个目的是评估能力 在金属中心的次级配位层中的强局部静电场影响金属的电子 结构和反应性分布。静电场在酶学和最近的计算研究中起着关键作用 提供了它们在金属酶中起作用的第一个迹象。脂氧合酶，蓝铜蛋白， 光系统II，以及血红素和非血红素Fe中心已经被不同地预测使用局部静电场， 促进电子转移、质子转移或质子耦合电子转移（PCET）。初步结果显示， 实验室已经模拟了酶组织电场的能力，这种能力对活性物质有利。 网站的化学我们的分子化合物中的这种静电预组织随后被证明可以调节O2和 与CuI离子的结合以及随后的分子间PCET化学反应的速率。拟议的研究将首先描述 在何种程度上静电场能够门PCET -代谢的根本重要性的过程。 初步数据中意想不到的趋势暗示了有趣的静电场效应，需要在 一种系统的方式。接下来，将探讨利用次级配位球静电效应的能力 稳定已被提议在O2处理过程中在各种单铜站点开发的关键中间体， 生物学预计静电效应将为稳定这些物种的能源格局提供有用的转变。 最后，提出了一种利用X射线鉴别次级配位球静电效应的新方法 吸收光谱和密度泛函理论的基础上，预期定向静电场将 调节XAS受体态的能量和强度。本研究计划的这一部分的广泛范围是 旨在提高我们在分子过渡金属系统中识别、调节和使用静电场的能力， 创造有效的仿生学所需要的。在本研究计划的第二部分，我们将调查 限制几何结构的簇化合物，以影响生物相关的N2固定化学。许多金属酶 使用多核活性位点来活化小分子，但努力模仿它们的结构和催化活性， 已经落后，大多数依赖于单核过渡金属络合物。研究的最新发展 固氮酶已经将限制几何双核位点鉴定为N2固定的可能位置。在 初步调查，我们已经利用了配体系统，能够限制两个金属中心的位置 被安置在大环框架内。这种复合物的二铁形式已被证明可以形成许多物种 这与固氮酶固氮的机制有关。拟议 工作将执行一个逐步的调查能力的限制几何diiron网站穿梭氮 沿着N2还原途径的底物。这两个部分合在一起，有望促进我们对 金属酶在生物学中进行一些最具挑战性的转化的方式。

项目成果

N-H Bond Formation at a Diiron Bridging Nitride.

在二铁桥氮化物上形成N-H键。

• DOI: 10.1002/anie.202006391
• 发表时间: 2020-08-24
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Zhang S;Cui P;Liu T;Wang Q;Longo TJ;Thierer LM;Manor BC;Gau MR;Carroll PJ;Papaefthymiou GC;Tomson NC
• 通讯作者: Tomson NC

Pyridyldiimine macrocyclic ligands: Influences of template ion, linker length and imine substitution on ligand synthesis, structure and redox properties

吡啶二亚胺大环配体：模板离子、连接基长度和亚胺取代对配体合成、结构和氧化还原性质的影响

• DOI: 10.1016/j.poly.2021.115044
• 发表时间: 2021
• 期刊: Polyhedron
• 影响因子: 2.6
• 作者: Thierer, Laura M.;Wang, Qiuran;Brooks, Sam H.;Cui, Peng;Qi, Jia;Gau, Michael R.;Manor, Brian C.;Carroll, Patrick J.;Tomson, Neil C.
• 通讯作者: Tomson, Neil C.

Probing Ligand Effects on the Ultrafast Dynamics of Copper Complexes via Midinfrared Pump-Probe and 2DIR Spectroscopies.

• DOI: 10.1021/acs.jpcb.1c06370
• 发表时间: 2021-11-11
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Weng, Wei;Weberg, Alexander B.;Gera, Rahul;Tomson, Neil C.;Anna, Jessica M.
• 通讯作者: Anna, Jessica M.

Oriented internal electrostatic fields: an emerging design element in coordination chemistry and catalysis.

• DOI: 10.1039/d2sc01715f
• 发表时间: 2022-05-18
• 期刊: CHEMICAL SCIENCE
• 影响因子: 8.4
• 作者: Weberg, Alexander B.;Murphy, Ryan P.;Tomson, Neil C.
• 通讯作者: Tomson, Neil C.

Interdependent Metal-Metal Bonding and Ligand Redox-Activity in a Series of Dinuclear Macrocyclic Complexes of Iron, Cobalt, and Nickel.

铁、钴和镍的一系列双核大环配合物中相互依赖的金属-金属键合和配体氧化还原活性。

• DOI: 10.1021/acs.inorgchem.9b02339
• 发表时间: 2020
• 期刊: Inorganic chemistry
• 影响因子: 4.6
• 作者: Wang,Qiuran;Zhang,Shaoguang;Cui,Peng;Weberg,AlexanderB;Thierer,LauraM;Manor,BrianC;Gau,MichaelR;Carroll,PatrickJ;Tomson,NeilC
• 通讯作者: Tomson,NeilC