Quantum wavepacket ab initio dynamical studies of hydrogen transfer catalysis in

氢转移催化的量子波包从头算动力学研究

基本信息

批准号：
8114978
负责人：
Srinivasan Sesha Iyengar
金额：
$ 21.66万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114978
关键词：
Active Sites Alcohol dehydrogenase Alcohols Aldehydes Amino Acid Substitution Amino Acids Animals Bacteria Biological Catalysis Cell Nucleus Chemicals Chemopreventive Agent Computer Simulation Computing Methodologies Coupling Deuterium Development Electrons Environment Enzyme Inhibition Enzymes Evolution Exhibits Fermentation Goals High temperature of physical object Human Hybrids Hydrogen Hydrogen Bonding Indiana Inflammatory Response Isotopes Kinetics Leukotriene Production Linoleic Acids Lipoxins Lipoxygenase Liver Malignant Neoplasms Mammals Mechanics Metals Methodology Methods Modification Molecular Mutagenesis Mutation Play Prevalence Procedures Process Proteins Protocols documentation Psyche structure Quantum Mechanics Reaction Role Series Staging System Techniques Time Tritium Universities Writing Yeasts abstracting base design electronic structure fascinate fatty acid oxidation lipoxygenase L-1 metalloenzyme molecular dynamics molecular mechanics oxidation particle prevent protein structure public health relevance quantum research study synthetic enzyme theories tumor

项目摘要

DESCRIPTION (provided by applicant): Quantum wavepacket ab initio dynamical studies of hydrogen transfer catalysis in enzymes Srinivasan S. Iyengar Indiana University Abstract This proposal deals with the fundamental molecular level description of hydrogen transfer processes in enzymes. Two enzymes are considered: (a) Soybean Lipoxygenase-1 (SLO-1) is a non-heme metalloenzyme that catalyzes oxidation of fatty acids. In mammals, lipoxygenase catalyzes the production of leukotrienes and lipoxins and plays an important role in inflammatory response. Inhibition of this enzyme inhibits tumor-genesis. Thus lipoxygenase has been proposed as a promising cancer chemopreventive agent. (b) Thermophilic alcohol dehydrogenase (ADH), facilitates conversion of alcohols to aldehydes and prevents accumulation of toxic alcohols in mammalian livers. These enzymes present an active challenge to computer simulation protocols since they exhibit unexpected hydrogen/deuterium/tritium kinetic isotope effects. The fundamental reason behind these isotope effects is believed to be based on quantum mechanical tunneling. The computational treatment proposed here utilizes a new time-dependent, first principles method, developed in the P.I.'s group. It allows efficient quantum dynamics of large systems through simultaneous dynamics of electrons and nuclei via a synergy between quantum wavepacket dynamics and ab initio molecular dynamics. In SLO-1, we will study the abnormal primary kinetic isotope effect seen in recent experiments, through simultaneous quantum mechanical dynamics of the tunneling hydrogen nucleus with classical dynamics of active site and surrounding amino acids, and concurrent determination of electronic structure using AIMD with QM/MM approximations. The detailed description undertaken here, through computational mutagenesis studies, will elucidate contributions from amino acid groups and the metal centers. For ADH, we will attempt to describe the fascinating secondary kinetic isotope effects in recent experiments which indicate coupling between primary (transferring) hydrogen atoms and secondary nuclei. The quantum dynamics approach will be generalized to treat multiple particles (primary hydrogens and secondary particles) in parallel with simultaneous classical dynamics of active site, and concurrent determination of electronic structure. This goal will be achieved through a series of proposed methodological advances. The studies will determine, at an unprecedented quantum dynamical level, the coupling between different nuclei in the enzyme active site. The effect of amino acid substitutions and metal center replacements will also be probed. Secondary isotope effects are a direct probe of the reaction coordinate. Hence, our approach will have impact on all hydrogen transfer reactions in biological and synthetic enzymes. PUBLIC HEALTH RELEVANCE: This proposal pertains to the development of new computational methods that will be utilized to conduct a fundamental molecular level study of hydrogen transfer processes in two biological enzymes: Soybean Lipoxygenase-1 (SLO-1) and high temperature thermophilic alcohol dehydrogenase (ADH). The computational methods are based on quantum mechanics and are especially designed to understand the implications of hydrogen tunneling on the function of these enzymes.

描述（由申请人提供）：从头开始的量子波袋从酶Srinivasan S. Iyengar S. Iyengar Indiana University中的氢转移催化的动力学研究摘要该提案涉及酶中氢转移过程的基本分子水平描述。考虑了两种酶：（a）大豆脂氧合酶-1（SLO-1）是一种非血红素金属酶，可催化脂肪酸的氧化。在哺乳动物中，脂氧酶催化白细胞和脂毒素的产生，并在炎症反应中起重要作用。抑制这种酶会抑制肿瘤生成。因此，已提出脂氧酶是一种有希望的癌症化学预防剂。（b）嗜热酒精脱氢酶（ADH），促进醇的转化为醛，并防止哺乳动物肝中有毒醇的积累。这些酶对计算机仿真方案提出了积极的挑战，因为它们表现出意外的氢/氘/tri虫动力学同位素效应。这些同位素效应背后的基本原因被认为是基于量子机械隧道的。这里提出的计算处理利用了P.I.组中开发的新的时间依赖性的第一原理方法。它通过量子波袋动力学和从头算分子动力学之间的协同作用，通过电子和核的同时动力学来实现大型系统的有效量子动力学。在SLO-1中，我们将通过在最近实验中观察到的异常原发动力学同位素效应，通过同时使用活性位点和周围氨基酸的经典动力学的隧穿氢核的量子机械动力学，并同时使用QM/MMMMMMMMMM近似值来确定AIMD的电子结构。这里通过计算诱变研究进行的详细描述将阐明氨基酸基团和金属中心的贡献。对于ADH，我们将尝试在最近的实验中描述引人入胜的次级动力学同位素效应，该实验表明原子（转移）氢原子与次级核之间耦合。量子动力学方法将被推广，以同时处理活性位点的经典动力学以及同时测定电子结构的多个颗粒（一级氢和次要颗粒）。这个目标将通过一系列建议的方法学进步来实现。研究将在空前的量子动力学水平上确定酶活性位点不同核之间的耦合。还将探测氨基酸取代和金属中心替换的影响。次级同位素效应是反应坐标的直接探针。因此，我们的方法将对生物学和合成酶中所有氢转移反应产生影响。公共卫生相关性：该提案与新的计算方法的开发有关，该方法将用于对两种生物学酶的氢转移过程进行基本分子水平研究：大豆脂氧酶-1（SLO-1）和高温嗜热醇脱氢酶（ADH）。计算方法基于量子力学，尤其是为了了解氢隧穿对这些酶功能的影响。