Simulation of Protein and Hydride Transfer in Enzymes

描述（由申请人提供）：本研究的广泛，长期目标是阐明酶催化中氢转移的基本原理和机制，并解决生物学重要系统中未解决的问题。这些目标将通过最近开发的混合量子-经典分子动力学方法来实现，该方法包括电子和核量子效应，以及整个溶剂化酶的运动。第一个具体目标是确定酶的结构和运动对催化的影响。第二个具体目标是阐明核量子效应如零点运动和氢隧穿在酶催化中的作用。其余三个具体目标针对三种酶反应解决这些问题，这些酶反应是根据其生物医学重要性和相关实验数据的可用性选择的。第三个特定目标集中在酶二氢叶酸还原酶（DHFR），这是原核生物和真核生物正常叶酸代谢所必需的。这种酶对于维持嘌呤、嘧啶和氨基酸的生物合成所需的四氢叶酸水平至关重要。DHFR在医学上是相关的，因为用有效的抗叶酸盐抑制DHFR已成功地用于癌症化疗。第四个具体目标集中在酶二氢酸脱氢酶（DHOD）。这种酶在嘧啶的生物合成中催化唯一的氧化还原反应，这是RNA和DNA合成所需的前体的供应。DHOD在医学上是相关的，因为抑制这种酶的免疫抑制作用已被用于治疗。第五个具体目标是脂氧合酶，它在植物和哺乳动物中起着许多重要作用。在哺乳动物中，脂氧合酶具有医学相关性，因为它们介导哮喘、动脉粥样硬化、牛皮癣、炎症性疾病和癌症生长等过程。

DESCRIPTION (provided by applicant): The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms of hydrogen transfer in enzyme catalysis and to address unresolved issues in biologically important systems. These objectives will be accomplished with a recently developed mixed quantum-classical molecular dynamics approach that includes electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The first specific aim is to determine the impact of enzyme structure and motion on catalysis. The second specific aim is to clarify the role of nuclear quantum effects such as zero point motion and hydrogen tunneling in enzyme catalysis. The remaining three specific aims address these issues for three enzyme reactions, which have been chosen on the basis of their biomedical importance and the availability of relevant experimental data. The third specific aim centers on the enzyme dihydrofolate reductase (DHFR), which is required for normal folate metabolism in prokaryotes and eukaryotes. This enzyme is essential for the maintenance of tetrahydrofolate levels required to support the biosynthesis of purines, pyrimidines, and amino acids. DHFR is medically relevant, in that inhibition of DHFR with potent antifolates has been used successfully in cancer chemotherapy. The fourth specific aim centers on the enzyme dihydroorotate dehydrogenase (DHOD). This enzyme catalyzes the only redox reaction in the biosynthesis of pyrimidines, which are required for the supply of precursors for RNA and DNA synthesis. DHOD is medically relevant, in that the immunosuppressive effects of inhibiting this enzyme have been used therapeutically. The fifth specific aim centers on lipoxygenase, which serves numerous vital roles in plants and mammals. In mammals, lipoxygenases are medically relevant, in that they mediate processes such as asthma, atherosclerosis, psoriasis, inflammatory diseases, and cancer growth.