Geometry of Charge Density as a Reporter on the Role of the Protein Scaffold in Enzymatic Catalysis: Electrostatic Preorganization and Beyond
Geometry of Charge Density as a Reporter on the Role of the Protein Scaffold in Enzymatic Catalysis: Electrostatic Preorganization and Beyond
复制标题
电荷密度几何作为蛋白质支架在酶催化中的作用的报告基因：静电预组织及其他
DOI：
10.1021/acs.jctc.2c01060
复制
发表时间：
2023
影响因子：
5.5
通讯作者：
Alexandrova, Anastassia N.
中科院分区：
文献类型：
--
作者：
Eberhart, Mark E.;Wilson, Timothy R.;Johnston, Nathaniel W.;Alexandrova, Anastassia N.
酶在蛋白质大分子中具有活性位点，这些蛋白质大分子具有多种多样的，通常令人难以置信的复杂和原子昂贵的结构。这是一个突出的问题，这些昂贵的支架可能在酶催化的作用。解决这个问题对于酶学和设计具有与最好的天然酶相匹配的功能的人工酶都是必不可少的。与动力学和振动运动促进反应相比，蛋白质硬化活性位点，以及长程静电（也称为静电预组织）都被认为是支架对催化的核心贡献。在这里，我们表明，所有这些影响不可避免地产生的量子力学的电子密度在活性位点，这反过来又定义了反应性的变化。因此，这些现象在根本上是不可分割的。电子密度的几何形状--一个标量场，其特征在于具有许多数学特征，如临界点--是酶催化作用的一个严格而方便的描述符，也是蛋白质作用的一个报告者。我们展示了如何可以分析这种几何形状，与反应障碍，并特别报告在酶的分子内电场。我们说明这些工具的静电preorganization在几个代表性的酶类，天然和人工的研究。我们强调这一方法的前瞻性。
Enzymes host active sites inside protein macromolecules, which have diverse, often incredibly complex, and atom-expensive structures. It is an outstanding question what the role of these expensive scaffolds might be in enzymatic catalysis. Answering this question is essential to both enzymology and the design of artificial enzymes with proficiencies that will match those of the best natural enzymes. Protein rigidifying the active site, contrasted with the dynamics and vibrational motion promoting the reaction, as well as long-range electrostatics (also known as electrostatic preorganization) were all proposed as central contributions of the scaffold to the catalysis. Here, we show that all these effects inevitably produce changes in the quantum mechanical electron density in the active site, which in turn defines the reactivity. The phenomena are therefore fundamentally inseparable. The geometry of the electron density–a scalar field characterized by a number of mathematical features such as critical points–is a rigorous and convenient descriptor of enzymatic catalysis and a reporter on the role of the protein. We show how this geometry can be analyzed, linked to the reaction barriers, and report in particular on intramolecular electric fields in enzymes. We illustrate these tools on the studies of electrostatic preorganization in several representative enzyme classes, both natural and artificial. We highlight the forward-looking aspects of the approach.