THEORETICAL STUDY OF AMIDE HYDROLYSIS

使用量子力学和经典的结合 方法学方面，我们正在研究碱催化的酰胺水解法。 该反应是许多酶促多肽裂解的典型反应。 过程和深入的研究因此可以增进我们的理解 一些重要的生物过程。我们表现出了很高的水平 从头算以获得气体的准确描述 小分子酰胺的相反应路径和反应能量学。我们 进行了蒙特卡罗模拟，模拟了放置在 显式水分子浴来计算溶剂对此的影响 反应。使用统计微扰理论和协议 由约根森介绍，我们计算了平均数的势 沿预定反应坐标的力。一些重要的事情 结果包括观察到一种显著的溶剂诱导 形成四面体中间体(Tet)的障碍，以及一个 过渡态向TET击穿的显著转变。 中对Tet形成步骤也进行了类似的计算 相应的酶反应(胰酶)。总体而言，我们有 与已有的实验数据取得了良好的一致性。我们计划 为了将我们的研究扩展到(1)显性极化，(2)a 系统的全耦合QM/MM表示。这两项增强功能 在潜在的理论模型中有望改进 结果的准确性以及它们的重要性可以被评估。这个 加州大学旧金山分校计算机图形实验室的图形设施 在我们的研究过程中被广泛使用。计算机程序 包括来自CGL的MidasPlus和来自我自己的ChemCam已经证明 对可视化反应的各个方面非常有帮助。对.的使用 中环线的设施对顺利完成 当前项目。

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.