THEORETICAL STUDY OF AMIDE HYDROLYSIS

酰胺水解的理论研究

• 批准号: 6119107
• 负责人: DIRK BAKOWIES
• 金额: $ 0.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6119107
• 关键词: biological products; biomedical resource; computers; enzymes; proteins

Using a combination of quantum-mechanical and classical methodology, we are investigating base catalyzed amide hydrolysis. This reaction is prototypical for many enzymatic peptide cleavage processes and a thorough study can therefore enhance our understanding of some important biological processes. We have performed high level ab initio calculations to obtain an accurate description of the gas phase reaction path and the reaction energetics for small amides. We have carried out Monte Carlo simulations for the reactants placed in a bath of explicit water molecules to calculate solvent effects on this reaction. Using statistical perturbation theory and a protocol introduced by Jorgensen, we have calculated the potentials of mean force along the predetermined reaction coordinate. Some important results include the observation of a significant solvent- induced barrier towards formation of the tetrahedral intermediate (TET), and a remarkable shift of the transition state towards TET breakdown. Similar calculations have been performed for the TET formation step in the corresponding enzymatic reaction (Trypsin). In general, we have achieved good agreement with the available experimental data. We plan to extend our studies to investigate (1) explicit polarization, (2) a fully coupled QM/MM representation of the system. Both enhancements in the underlying theoretical model are expected to improve the accuracy of the results, and their importance can be assessed. The graphics facilities of the Computer Graphics Laboratory at UCSF have been used extensively in the course of our studies. Computer programs including MidasPlus (from CGL) and CHEMCAM (from myself) have prove very helpful to visualize various aspects of the reaction. The use of the CGL facilities is essential for successful completion of the current project.

结合使用量子力学和经典 方法论中，我们正在研究碱催化的酰胺水解。 该反应是许多酶促肽裂解的典型反应 因此，过程和彻底的研究可以增强我们的理解 一些重要的生物过程。 我们表现​​出了高水平 从头计算以获得气体的准确描述 小酰胺的相反应路径和反应能量学。 我们 对放置在反应器中的反应物进行了蒙特卡罗模拟 显式水分子浴以计算溶剂对此的影响 反应。 使用统计扰动理论和协议 由 Jorgensen 引入，我们计算了均值的潜力 沿着预定反应坐标的力。 一些重要的 结果包括观察到显着的溶剂诱导 形成四面体中间体（TET）的势垒，以及 过渡状态向 TET 崩溃的显着转变。 对 TET 形成步骤进行了类似的计算 相应的酶促反应（胰蛋白酶）。 一般来说，我们有 与现有的实验数据取得了良好的一致性。 我们计划 扩展我们的研究以调查（1）显性极化，（2） 系统的完全耦合 QM/MM 表示。 两项增强功能 在基础理论模型中预计将改善 可以评估结果的准确性及其重要性。 这 加州大学旧金山分校计算机图形实验室的图形设施有 在我们的学习过程中被广泛使用。 计算机程序 包括 MidasPlus（来自 CGL）和 CHEMCAM（来自我自己）已经证明 非常有助于可视化反应的各个方面。 使用 CGL 设施对于成功完成 当前项目。