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Theortical study of free energy landscapes of biological macromolecules by the hybrid computation for electronic structure and molecular structure sampling

电子结构与分子结构采样混合计算生物大分子自由能图谱的理论研究

基本信息

批准号：
18370063
负责人：
NAKAMURA Haruki
金额：
$ 3.47万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

1. Development of the hybrid-QM/MM calculation methodThe hybrid-QM/MM method combines the advantages in the quantum chemistry and the molecular mechanics for the accurate simulation of a protein-solvent system, by treating the essential region of a protein by quantum mechanics and applying the classical Newtonian equations to the rest of the target system. We have developed a software program for the novel hybrid-QM/MM simulations.2. The hybrid-QM/MM simulation study on the mechanism of proline cis-trans isomerization of human Pin 1 proteinPin1 is one of human peptidyl-prolyl isomerases, which catalyzes the cis-trans isomerization of a proline residue. This enzyme is associated with a cancerous change of cells and apoptosis, and its close relationships with Alzheimer's disease has also been reported. We have studied the isomerization mechanism of this enzyme, by calculating the electronic structure of the peptide bond at the proline in the ligand and sampling the protein and the surrou … More nding solvent molecular structures. Finally, we have revealed the reaction and conformation free energy change including the entropy effect.3. Molecular orbital and molecular dynamics studies of the reaction mechanism of the enzyme-catalyzed hydrolysisTo understand how the conformational factors are related to enzyme-catalyzed hydrolysis by lipases, conformational analysis was performed by molecular dynamics simulations for the tetrahedral intermediates bound to lipases. Consequently, we found the similar conformational preference to the intermediates of the transacylation of methyl acetate computed by molecular orbital theory. In molecular dynamics simulation for the two-metal mechanism of the RNase H catalysis, the distance between two Mg^<2+> ions in the active site drifted apart due to the electrostatic repulsion, resulting in the disruption of the active site. Density functional calculation shows that esters of cyclopropanecarboxylic acid demonstrate a substantial increase in stability under base-catalyzed hydrolysis compared to other esters. Less

1. 混合QM/MM计算方法的发展混合QM/MM方法结合了量子化学和分子力学的优点，通过量子力学处理蛋白质的基本区域并将经典牛顿方程应用于目标系统的其余部分，从而精确模拟蛋白质-溶剂系统。我们开发了一个用于新颖的混合QM/MM模拟的软件程序。2．人Pin 1蛋白脯氨酸顺反异构化机制的Hybrid-QM/MM模拟研究Pin1是人肽基脯氨酰异构酶之一，催化脯氨酸残基的顺反异构化。这种酶与细胞的癌变和细胞凋亡有关，也有报道称其与阿尔茨海默病有密切关系。我们通过计算配体中脯氨酸肽键的电子结构并对蛋白质和周围溶剂分子结构进行采样，研究了这种酶的异构化机制。最后，我们揭示了反应和构象自由能的变化，包括熵效应。3．酶催化水解反应机理的分子轨道和分子动力学研究为了了解构象因素与脂肪酶酶催化水解的关系，通过分子动力学模拟对与脂肪酶结合的四面体中间体进行构象分析。因此，我们发现通过分子轨道理论计算的乙酸甲酯转酰基中间体具有相似的构象偏好。在RNase H催化双金属机理的分子动力学模拟中，由于静电斥力，活性位点中两个Mg^2+离子之间的距离发生漂移，导致活性位点的破坏。密度泛函计算表明，与其他酯相比，环丙烷甲酸的酯在碱催化水解下稳定性显着提高。较少的