COMPUTATIONAL CHEMISTRY OF ALDEHYDE DEHYDROGENASES

醛脱氢酶的计算化学

• 批准号: 7956068
• 负责人: TROY WYMORE
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956068
• 关键词: Acetaldehyde; Aldehydes; Biomedical Research; Carboxylic Acids; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Funding; Goals; Grant; High Performance Computing; Institution; Mechanics; Metabolism; Methods; Molecular; Play; Potential Energy; Reaction; Research; Research Personnel; Resources; Role; Sequence Analysis; Site-Directed Mutagenesis; Source; Structure; Surface; United States National Institutes of Health; abstracting; aldehyde dehydrogenases; computational chemistry; design; molecular dynamics; quantum; research study; thioester

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. molecular dynamics aldehyde dehydrogenase metabolism Abstract: The function of enzymes are determined by many interactions that can be hard to dissect experimentally and as such computer models that reproduce experiments can give atomic level details for such observables. These interactions are also important for the rational design of inhibitors of enzyme function. The goal of the proposed research is a detailed understanding of the catalytic mechanism of aldehyde dehydrogenase (ALDH) conversion of aldehyde to its corresponding carboxylic acid through the use of computational chemistry calculations. These calculations include examination of ground state structures of holo-form ALDH2, acetaldehyde in the Michaelis complex with ALDH, and the thioester intermediate state with molecular dynamics (MD) simulations. In addition, potential energy surfaces of key reaction steps of ALDH2 will be calculated using a quantum mechanical/molecular mechanical (QM/MM) method. These calculations will determine the structural and dynamics roles that residues play in this catalytic reaction. Finally, by integrating these calculation results with those from sequence analysis and site-directed mutagenesis experiments, we intend to understand the molecular factors that influence all ALDHs.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 分子动力学乙醛脱氢酶代谢摘要：酶的功能是由许多相互作用决定的，这些相互作用很难在实验上进行分析，因此，重现实验的计算机模型可以为这些可观察到的信息提供原子水平的细节。这些相互作用对于酶功能抑制剂的合理设计也很重要。拟议的研究的目标是通过使用计算化学计算的醛脱氢酶（ALDH）转化醛到其相应的羧酸的催化机制的详细了解。这些计算包括检查的基态结构的全息形式ALDH 2，乙醛在米氏络合物与ALDH，和硫酯中间态的分子动力学（MD）模拟。此外，ALDH 2的关键反应步骤的势能面将使用量子力学/分子力学（QM/MM）方法计算。这些计算将确定残基在该催化反应中所起的结构和动力学作用。最后，通过整合这些计算结果与那些从序列分析和定点突变实验，我们打算了解影响所有ALDH的分子因素。