DFT and DFT/MM Investigations of the Fe(III) Center in Nitrile Hydratase

佛罗里达大学的奈杰尔理查兹在理论和计算化学计划和分子生物物理计划的支持下，对腈水合酶（NHase）进行了一系列量子力学研究，NHase是一种具有商业意义的非血红素、含Fe（III）的酶。 该项目有三个具体目标：（1）评估密度泛函理论（DFT）方法在预测作为NHase金属中心模型的Fe（III）络合物的自旋状态偏好中的效用，（2）使用INDO/S半经验模型和混合DFT/分子力学（MM）的组合来模拟作为NHase金属中心模型的Fe（III）络合物的紫外-可见光谱力场方法，以及（3）研究DFT/MM计算在探测NHase Fe（III）活性中心的电子结构和酶机制中的应用。 NHase的理论描述预计将影响多个领域的研究。 首先，腈水合酶在立体化学复杂化合物的“绿色”合成中具有潜在的应用，特别是如果底物特异性可以基于结构和机理信息进行重新设计。 接下来，深入了解金属中心在催化中的作用，以及它与蛋白质的相互作用，有望刺激合理发现用于商业上重要的腈水合的新型无机催化剂。 最后，建模的结构和反应性的非血红素Fe（III）-中心在NHase将是一个强大的测试现代混合量子力学分子力学方法和密度泛函理论技术建模金属酶的效用。 理论方法的最新进展为含过渡金属的酶的结构、反应和催化提供了新的计算研究的可能性，这些酶通常介导初级和次级代谢产物生物合成的关键步骤。 在本项目中，将使用现代计算方法来计算这些酶的性质，预计这些酶在使用代谢工程的药物发现和使用生物技术方法的工业化学合成中具有未来的重要性。

Nigel Richards of the University of Florida is supported by the Theoretical and Computational Chemistry Program and the Molecular Biophysics Program to perform a series of quantum mechanical studies on nitrile hydratase (NHase), a non-heme, Fe(III)-containing enzyme of commercial significance. The project has three specific aims: (1) to evaluate the utility of density functional theoretical (DFT) methods in predicting the spin-state preferences of Fe(III) complexes that are models for the NHase metal center, (2) to model the UV-visible spectroscopy of Fe(III) complexes that are models of the NHase metal center using a combination of the INDO/S semiempirical model and hybrid DFT/molecular mechanics (MM) force field methods, and (3) to investigate the utility of DFT/MM calculations in probing the electronic structure of the NHase Fe(III) active site and the enzyme mechanism. The theoretical description of NHase is expected to impact research in several areas. First, NHase has potential applications in the "green" synthesis of stereochemically complex compounds, particularly if substrate specificity can be re-engineered on the basis of structural and mechanistic information. Next, insight into the role of the metal center in catalysis, and its interactions with the protein, are expected to stimulate the rational discovery of novel inorganic catalysts for the hydration of commercially important nitriles. Finally, modeling the structure and reactivity of the non-heme Fe(III)-center in NHase will be a robust test of the utility of modern hybrid quantum mechanical molecular mechanics methods and density-functional theory techniques for modeling metalloenzymes. Recent advances in theoretical methods have opened the possibility of new computational studies into the structure, reactions, and catalysis of transition metal-containing enzymes, which often mediate critical steps in the biosynthesis of both primary and secondary metabolites. In this project, modern computational approaches will be used to calculate the properties of these enzymes, which are expected to have future importance in pharmaceutical discovery using metabolic engineering, and industrial chemical synthesis using biotechnological methods.