Modelling Enzymatic Electrostatic Field Effects with Coordination Chemistry

在理解内部静电场的程度方面存在着根本性的差距 金属酶能够影响含过渡金属的辅因子的反应性。一 越来越多的证据表明，静电场是一个重要的 酶活性的一部分，但迄今为止，只有理论模型已经评估了这种 金属酶活性部位的静电效应。这种持续存在 知识差距是一个关键的缺陷，在理解的手段， 金属酶能够进行强键官能化反应，如N2 还原为NH 3和选择性C-H键氧化。在这方面的总体目标 应用程序是合成模型化合物，将允许的幅度和方向 与金属酶介导的关键步骤相关的静电场 转变将进行研究以检验中心假设，即强有力的， 局部的静电场改变了原子内部的价电子分布， 金属-基质相互作用，将反应性导向基质并催化键合 活化反应这一假设是根据两种文献提出的， 来自有机金属和酶学界的先例以及产生的初步数据 在本申请人的实验室中，其包括能够 稳定肽基甘氨酸α-羟基化中CuM位点的单核Cu：O2类似物 单加氧酶（PHM）的影响的方式一致的强，局部 静电场在这些背景信息的指导下，中心假设将是 通过首先创建模型复合物的库进行测试，其中非路易斯酸性带电残基 附加在中心金属中心的次级配位层中。合成 这些配体的多功能性将允许系统地改变带电配体的位置。 相对于金属中心的活性位点的残基。接下来，振动斯塔克光谱 将被用来量化的静电场强度内的基板结合口袋， 模型复杂。这些数据与配位化学研究的结合， 对O2-、NO-和N2-结合模型系统的反应性研究将用来证明这种能力 改变金属化合价歧管内的电子分布 配合物总的来说，这项工作补充了PI更广泛的研究计划，重点是 寻求控制过渡金属反应性的全新方法 复合物;该计划包括一系列的调查到使用静电场， 影响配位化学和催化以及多核的合成 簇络合物，其模拟在非均相催化剂上发生的表面化学。的 在本申请中描述的方法在申请人看来是创新的，因为它 提供了一种直接的方法来控制和测量 强，局部，静电场，同时使用这些数据来理解的行动， 金属酶这项研究是有意义的，因为它有望提供数据。 这将有助于了解酶催化的起源。

There is a fundamental gap in understanding the degree to which electrostatic fields within metalloenzymes are able to influence the reactivity of transition metal-containing cofactors. A growing body of evidence implicates electrostatic fields as the origin of a significant portion of enzymatic activity, but to date, only theoretical models have evaluated such electrostatic effects at the active sites of metalloenzymes. The continued existence of this knowledge gap represents a critical shortcoming in understanding the means by which metalloenzymes are able to perform strong-bond functionalization reactions, like N2 reduction to NH3 and selective C–H bond oxidation. The overall objective in this application is to synthesize model compounds that will allow the magnitude and direction of electrostatic fields to be correlated to critical steps in metalloenzyme-mediated transformations. Research will be performed to test the central hypothesis, that strong, local, electrostatic fields alter the valence electron distribution within metal-substrate interactions, directing reactivity to the substrate and catalyzing bond activation reactions. This hypothesis has been formulated on the basis of both literature precedent from the organometallic and enzymology communities as well as preliminary data produced in the applicant’s laboratory, which includes the synthesis of a new ligand framework capable of stabilizing a mononuclear Cu:O2 analog of the CuM site in peptidylglycine α-hydroxylating monooxygenase (PHM) in a manner consistent with the influence of strong, local electrostatic fields. Guided by this background information, the central hypothesis will be tested by first creating a library of model complexes in which non-Lewis acidic charged residues are appended in the secondary coordination sphere of a central metal center. The synthetic versatility of these ligands will allow for systematic changes to the location of the charged residues with respect to the active-site of the metal center. Next, vibrational Stark spectroscopy will be used to quantify the electrostatic field strength within the substrate-binding pocket of the model complexes. The union of these data with investigations into coordination chemistry and reactivity studies on O2-, NO-, and N2-bound model systems will be used to demonstrate the ability of charged residues to shift the electron distribution within the valence manifold of metal complexes. Overall, this work complements the PI’s broader research program focused on seeking fundamentally new methods for controlling the reactivity of transition metal complexes; this program includes a range of investigations into the use of electrostatic fields to influence coordination chemistry and catalysis as well as the synthesis of multinuclear cluster complexes that model the surface chemistry occurring on heterogenous catalysts. The approach described in this application is innovative, in the applicant’s opinion, because it provides a straight-forward means of both controlling and measuring the magnitude of strong, local, electrostatic fields, while using these data to understand the action of metalloenzymes. The proposed research is significant, because it is expected to provide data that will contribute to understanding of the origin of enzymatic catalysis.