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

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本质区域，并将经典的牛顿方程应用于目标系统的其余部分，从而准确地模拟了蛋白质-溶剂体系。我们开发了用于新型混合QM/MM模拟的软件程序。人Pin-1蛋白脯氨酸顺反异构化机理的混合QM/MM模拟研究Pin1是一种人肽基-脯氨基异构酶，催化脯氨酸残基的顺反异构化。这种酶与细胞癌变和细胞凋亡有关，它与阿尔茨海默病的密切关系也已有报道。我们通过计算配基中脯氨酸肽键的电子结构，并对蛋白质和…进行采样，研究了该酶的异构化机理更多的溶剂分子结构。最后，我们揭示了反应自由能和构象自由能的变化，其中包括了熵效应。分子轨道和分子动力学研究酶促水解的反应机理为了了解构象因子与脂肪酶的酶促水解的关系，对脂肪酶结合的四面体中间体进行了构象分析。因此，我们发现用分子轨道理论计算的乙酸甲酯转酰化反应的中间体具有相似的构象偏好。在RNaseH催化双金属机理的分子动力学模拟中，由于静电斥力，活性中心的两个镁离子之间的距离发生漂移，导致活性中心的破坏。密度泛函计算表明，与其他酯相比，环丙烷羧酸酯在碱催化下的稳定性有很大提高。较少

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