Modeling Modern Concepts in Metalloenzyme Active Site Reactivity

项目摘要 这门化学的首要目标是开发仿生过渡金属化学的新途径 金属酶活性部位的模型化方法。这项工作分为两个部分。第一个目标是评估能力 在金属中心的次级配位球中产生强烈的局部静电场，以影响金属的电子。 结构和反应性分布。静电场在酶学和最近的计算研究中扮演着重要的角色 已经提供了第一个迹象，表明它们在金属酶中起作用。脂肪氧合酶，蓝铜蛋白， 光系统II，以及血红素和非血红素铁中心都被不同地预测使用局部静电场来 促进电子转移、质子转移或质子耦合电子转移(PCET)。来自我们的初步结果 实验室模拟了酶组织电场的能力，以一种对活动者有利的方式 场地的化学反应。然后，我们的分子化合物中的这种静电预组织被证明调节两个O2 与CuI离子的结合以及随后的分子间PCET化学的速率。拟议的研究将首先描述 静电场能够触发PCET的程度--这是一个对新陈代谢至关重要的过程。 初步数据中的意外趋势暗示了有趣的静电场效应，需要在 一种有系统的时尚。接下来，我们将探讨利用二次配位球进行静电效应的能力 为了稳定在氧气加工过程中被提议在不同的单一铜地点开发的关键中间体 生物学。静电效应有望在能量格局中为稳定这些物种提供有用的转变。 最后，提出了一种利用X射线识别二次配位球静电效应的新方法 吸收光谱和密度泛函理论，基于定向静电场将 调整XAS受主能级的能量和强度。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、调整和使用静电场的能力 创造有效的仿生学所需的。在这个研究计划的第二部分，我们将调查 受约束的几何构型簇合物以影响生物相关的氮气固定化学。多种金属酶 利用多核活性中心进行小分子活化，但努力模拟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。生物多样性研究的最新进展 固氮酶已经确定限制几何双核位置作为氮气固定的可能位置。在……里面 初步研究，我们已经利用了一种能够限制两个金属中心位置的配体系统 被安置在一个大循环框架内。这种复合体的双铁版本已被证明形成了许多物种 这与已提出的在固氮酶上固定氮气的机制有关。建议数 工作将对受限几何双铁位置穿梭氮的能力进行循序渐进的调查 沿着氮气还原路径的底物。这两个部分将共同推动我们对 金属酶在生物学中执行一些最具挑战性的转化的方式。

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.