Modelling Enzymatic Electrostatic Field Effects with Coordination Chemistry

在理解静电场在多大程度上存在着根本性的差距 金属酶能够影响含过渡金属辅因子的反应活性。一个 越来越多的证据表明静电场是一种重要的 部分酶活性，但到目前为止，只有理论模型对此进行了评估 金属酶活性部位的静电效应。这一现象的持续存在 知识差距代表着在理解通过什么方式 金属酶能够执行像氮气一样的强键官能化反应 还原为NH3和选择性的C-H键氧化。这个项目的总体目标是 应用是合成模型化合物，它将允许大小和方向 与金属酶介导的关键步骤相关的静电场 变形。将进行研究，以检验中心假设，即强有力的， 局域静电场改变了内部的价电子分布 金属-底物相互作用，引导底物的反应性和催化键 活化反应。这一假设是在两个文献的基础上提出的 来自有机金属和酶学社区的先例以及产生的初步数据 在申请人的实验室中，这包括合成一种新的配体框架，能够 肽甘氨酸α-羟化反应中CUM位的单核铜氧类似物的稳定 单加氧酶(PHM)以一致的方式影响较强、局部 静电场。在这一背景信息的指导下，中心假设将是 通过首先创建一个模型络合物文库进行测试，在该库中非Lewis酸性带电残基 被附加在中心金属中心的二次配位球体中。合成材料 这些配体的多功能性将允许系统地改变带电的位置 相对于金属中心活性中心的残基。接下来，振动斯塔克光谱学 将用于量化衬底结合袋内的静电场强度 模型复合体。这些数据与对配位化学和 我们将用O2-、NO-和N2束缚的模型体系的反应性研究来证明这种能力 来改变金属价态中的电子分布 复合体。总体而言，这项工作是对PI关注的更广泛研究计划的补充 寻求控制过渡金属反应性的新方法 该计划包括对静电场的使用进行一系列调查，以 影响配位化学和催化以及多核化合物的合成 模拟发生在多相催化剂上的表面化学的簇合物。这个 在申请人看来，本申请中描述的方法是创新的，因为它 提供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 金属酶。这项拟议的研究意义重大，因为它有望提供数据 这将有助于理解酶催化的起源。

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.