Biomolecular Interactions and Enzymatic Processes
生物分子相互作用和酶促过程
基本信息
- 批准号:6780331
- 负责人:
- 金额:$ 26.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-09-30 至 2008-03-31
- 项目状态:已结题
- 来源:
- 关键词:bioinformaticscatalystcomputational biologycomputer program /softwarecomputer simulationconformationcysteine endopeptidasesenzyme activityenzyme structureintermolecular interactionionic bondisomerasemathematical modelmethod developmentmodel design /developmentmolecular dynamicsmolecular polaritymolecular rearrangementphotochemistryphysical modelprotein structure functionquantum chemistrysolutionsstructural biologythymidylate synthase
项目摘要
DESCRIPTION (provided by applicant): A multi-faceted research project is directly aimed at computational studies of enzymatic processes in aqueous solution. The theoretical approach centers on molecular dynamics simulations of enzymatic systems using combined quantum mechanical and molecular mechanical (QM/MM) methods. To achieve greater accuracy, we propose to further develop a mixed molecular orbital-valence bond (MOVB) method for simulation of enzyme reactions and sampling of the reaction pathway. In addition, we plan to implement a semi-empirical density functional theory for combined QM/MM calculations, which will significantly expand the scope of QM/MM applications to enzymatic systems, including metailoenzymes. A major thrust is to provide a deeper understanding of the remarkable catalytic power of enzymes. Our approach is to seek general catalytic principles, by examining individual enzymatic systems that share common features, but have different biological functions. In particular, the hydrolytic cysteine protease, human cathepsin K, and alanine and glutamate racemases, will be investigated in detail to understand substrate binding, reaction mechanism, and free energy profiles. Inhibitors of cathepsin K can reduce bone resorption, providing a promising therapeutic target for the treatment of osteoporosis and rheumatoid arthritis, while amino acid racemases are essential in the synthesis of the peptidoglycan layer of bacteria cell walls, rendering them attractive targets for inhibitors. The proposed computational study will provide insight into the mechanism of acid/base catalysis of these two important classes of enzymes. In addition, the dynamic conformational changes in thymidylate synthase (TS), that take place throughout the many-steps of the enzymatic reaction, will be studied. TS catalyzes the de novo synthesis of dTMP nucleotide for DNA synthesis, which has been extensively investigated experimentally. The proposed study will provide a deeper understanding of the roles of protein dynamic conformation change in the function of thymidylate synthase, and the results will be of general importance in enzyme catalysis.
描述(由申请人提供):一个多方面的研究项目直接针对水溶液中酶过程的计算研究。理论方法集中在酶系统的分子动力学模拟使用结合量子力学和分子力学(QM/MM)方法。为了达到更高的准确性,我们建议进一步发展混合分子轨道价键(MOVB)方法模拟酶反应和反应途径的采样。此外,我们计划实施一个半经验的密度泛函理论结合QM/MM计算,这将显着扩大范围的QM/MM应用酶系统,包括metailoenzymes。一个主要的推动力是提供一个更深入的了解显着的催化能力的酶。我们的方法是通过检查具有共同特征但具有不同生物学功能的单个酶系统来寻求一般催化原理。特别是,水解半胱氨酸蛋白酶,人组织蛋白酶K,丙氨酸和谷氨酸消旋酶,将详细研究,以了解底物结合,反应机制和自由能的档案。组织蛋白酶K的抑制剂可以减少骨吸收,为骨质疏松症和类风湿性关节炎的治疗提供了一个有前途的治疗靶点,而氨基酸消旋酶在细菌细胞壁的肽聚糖层的合成中是必不可少的,使它们成为抑制剂的有吸引力的靶点。拟议的计算研究将提供深入了解这两个重要类别的酶的酸/碱催化的机制。此外,在胸苷酸合成酶(TS),发生在整个酶促反应的许多步骤的动态构象变化,将进行研究。TS催化用于DNA合成的dTMP核苷酸的从头合成,这已被广泛地实验研究。该研究为进一步了解蛋白质动态构象变化在胸苷酸合成酶功能中的作用提供了新的思路,其结果在酶催化研究中具有重要意义。
项目成果
期刊论文数量(0)
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JIALI GAO其他文献
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{{ truncateString('JIALI GAO', 18)}}的其他基金
Biomolecular Interactions and Enzymatic Processes
生物分子相互作用和酶促过程
- 批准号:
10462598 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
BIOMOLECULAR INTERACTIONS AND ENZYMATIC PROCESSES
生物分子相互作用和酶促过程
- 批准号:
2900767 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
Biomolecular Interactions and Enzymatic Processes
生物分子相互作用和酶促过程
- 批准号:
7036497 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
Biomolecular Interactions and Enzymatic Processes
生物分子相互作用和酶促过程
- 批准号:
7800956 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
Biomolecular Interactions and Enzymatic Processes
生物分子相互作用和酶促过程
- 批准号:
8922816 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
Biomolecular Interactions and Enzymatic Processes
生物分子相互作用和酶促过程
- 批准号:
7215659 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
BIOMOLECULAR INTERACTIONS AND ENZYMATIC PROCESSES
生物分子相互作用和酶促过程
- 批准号:
2684981 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
Biomolecular Interactions and Enzymatic Processes
生物分子相互作用和酶促过程
- 批准号:
10220985 - 财政年份:1992
- 资助金额:
$ 26.87万 - 项目类别:
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