Quantum wavepacket ab initio dynamical studies of hydrogen transfer catalysis in

描述（由申请人提供）：酶中氢转移催化的量子波包从头算动力学研究Srinivasan S. Iyengar Indiana University摘要本提案涉及酶中氢转移过程的基本分子水平描述。两种酶被考虑：(a)大豆脂氧化酶-1 （SLO-1）是一种非血红素金属酶，催化脂肪酸氧化。在哺乳动物中，脂氧合酶催化白三烯和脂毒素的产生，并在炎症反应中起重要作用。抑制这种酶可以抑制肿瘤的发生。因此，脂氧合酶被认为是一种很有前途的癌症化学预防剂。(b)嗜热性醇脱氢酶（ADH），促进醇转化为醛，防止有毒醇在哺乳动物肝脏中积累。这些酶对计算机模拟方案提出了积极的挑战，因为它们表现出意想不到的氢/氘/氚动力学同位素效应。这些同位素效应背后的根本原因被认为是基于量子力学隧道效应。这里提出的计算处理利用了一种新的时间相关的第一性原理方法，该方法是在P.I.中发展起来的的组。它通过量子波包动力学和从头算分子动力学之间的协同作用，通过电子和原子核的同步动力学来实现大型系统的有效量子动力学。在SLO-1中，我们将通过隧道氢核的量子力学动力学与活性位点和周围氨基酸的经典动力学同时进行，并使用AIMD与QM/MM近似同时测定电子结构，研究最近实验中看到的异常初级动力学同位素效应。通过计算诱变研究，这里进行的详细描述将阐明氨基酸群和金属中心的贡献。对于ADH，我们将尝试描述最近实验中令人着迷的次级动力学同位素效应，这些效应表明初级（转移）氢原子和次级原子核之间的耦合。量子动力学方法将被推广到并行处理多个粒子（初级氢和次级粒子），同时进行活性位点的经典动力学，并同时确定电子结构。这一目标将通过提出的一系列方法进步来实现。这些研究将在前所未有的量子动力学水平上确定酶活性位点不同核之间的耦合。还将探讨氨基酸取代和金属中心取代的影响。次生同位素效应是反应坐标的直接探测。因此，我们的方法将对生物酶和合成酶中的所有氢转移反应产生影响。

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.