THEORETICAL STUDY OF AMIDE HYDROLYSIS

结合量子力学和经典力学 方法，我们正在研究碱催化酰胺水解。 该反应是许多酶促肽裂解的原型 过程和深入的研究，因此可以提高我们的理解 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 相反应路径和反应能量学。 我们 已经进行了蒙特卡罗模拟的反应物放置在一个 浴明确的水分子来计算溶剂的影响， 反应 利用统计微扰理论和一个协议 由Jorgensen引入，我们计算了平均势 迫使沿着预定的反作用坐标。 一些重要 结果包括观察到显著的溶剂诱导的 形成四面体中间体（泰特）的势垒，以及 过渡态向泰特击穿方向的显著转变。 已经对图1中的泰特形成步骤进行了类似的计算。 相应的酶促反应（胰蛋白酶）。 总的来说，我们有 取得了良好的协议与现有的实验数据。 我们计划 为了扩展我们的研究，研究（1）显式极化，（2） 系统的完全耦合QM/MM表示。 两项增强功能 在基本的理论模型，预计将改善 可以评估结果的准确性及其重要性。 的 加州大学旧金山分校计算机图形实验室的图形设备 在我们的研究过程中被广泛使用。 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。

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.