Electronic Structure and Reactions of Fe-oxo Enzymes

描述(申请人提供)：铁-氧和铁-过氧基酶活性中心的铁络合物的电子结构计算现在对理解这些体系的物理性质和反应化学有重要的贡献。我们使用高质量的量子力学密度泛函理论(DFT)方法来描述和分析活性中心的性质，并将其与较长范围的蛋白质和溶剂环境的静电表示联系起来。我们的长期目标是详细了解化学键、反应能量学和途径，并与实验结构、光谱和动力学研究密切联系。(1)这些密度泛函方法将被用来计算铁-氧和铁-过氧基酶的关键中间体的精确几何构型、能量和质子化状态。感兴趣的特定酶是I类核糖核苷酸还原酶(RNRs)、甲烷单加氧酶(MMOS)、甲苯单加氧酶(Tolos)和Rieske加氧酶。(2)将与一些基于X射线、光学和电子/核子的光谱仪建立详细的联系。(3)对这些酶的反应路径进行了评估，并与实验动力学进行了比较。(4)将对新的理论/计算方法进行测试并与实验进行比较，以进一步发展现代化学理论的能力和分析能力。RNRs催化核糖核苷酸向脱氧核糖核苷酸的转化，这是DNA合成中第一个必需的步骤，通常也是限速步骤。因此，RNR是抗癌、抗病毒和抗菌治疗的药物靶点。MMOS、Tolos和Rieske加氧酶在有机污染物的解毒方面具有巨大的潜力，并且有望成为寻找环境无毒的方法来合成有价值的化学品的指南。对这些酶机制的更好理解应该有助于实现这些目标的实验工作。

DESCRIPTION (provided by applicant): Electronic structure calculations for the iron complexes at the active sites of iron-oxo and iron-peroxo based enzymes are now making an important contribution to understanding the physical properties and reaction chemistry of these systems. We use high-quality quantum mechanical density functional theory (DFT) methods to describe and analyze active site properties, and link this to an electrostatics-based representation of the longer range protein and solvent environment. Our long term goal to develop a detailed understanding of chemical bonding, reaction energetics and pathways, making a close connection with experimental structural, spectroscopic, and kinetics studies. (1) These DFT methods will be used to calculate accurate geometries, energies, and protonation states for critical intermediates of iron-oxo and iron-peroxo enzymes. The specific enzymes of interest are Class I ribonucleotide reductases (RNRs) methane monooxygenases (MMOs), toluene monoxygenases (Tolos) and Rieske oxygenases. (2) Detailed connections will be made to a number of X-ray, optical and electron/nuclear based spectroscopies. (3) Reaction pathways for these enzymes will be evaluated and compared with experimental kinetics. (4) New theoretical/computational methods will be tested and compared with experiment to further develop the power and analysis capabilities of modem chemical theory. RNRs catalyze the transformation of ribonucleotides to deoxyribonucleotides, the first required and often rate limiting step in DNA synthesis. Consequently, RNR is a drug target in anticancer, antiviral, and antibacterial therapies. MMOs, Tolos, and Rieske oxygenases have great potential for the detoxification of organic pollutants, and are promising as guides to finding environmentally nontoxic methods for the synthesis of valuable chemicals. A better understanding of these enzyme mechanisms should aid experimental work toward these goals.