COMPUTATIONAL CHEMISTRY OF ALDEHYDE DEHYDROGENASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 分子动力学乙醛脱氢酶代谢摘要：酶的功能是由许多很难用实验分析的相互作用决定的，因此，复制实验的计算机模型可以给出这些可观察到的原子水平的细节。这些相互作用对于酶功能抑制剂的合理设计也很重要。这项研究的目的是通过计算化学计算详细了解乙醛脱氢酶(ALDH)将乙醛转化为相应的羧酸的催化机理。这些计算包括用分子动力学(MD)模拟考察了全息ALDH2的基态结构、乙醛与ALDH形成的米氏络合物以及硫酯中间态。此外，还将用量子力学/分子力学(QM/MM)方法计算ALDH2关键反应步骤的势能面。这些计算将确定残基在这一催化反应中所起的结构和动力学作用。最后，通过将这些计算结果与序列分析和定点突变实验的结果相结合，我们打算了解影响所有ALDH的分子因素。

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.