中文摘要：

甲基花生四烯基氟代膦酸酯（MAFP）是脂肪酰胺水解酶（FAAH）的一个抑制剂.FAAH的丝氨酸241（Ser241）-丝氨酸217（Ser217）-赖氨酸142（Lys142）催化三联体被MAFP膦酰化后将导致FAAH失活.本文采用B3LYP/6-311G（d,p）和MP2/6-311G（d,p）方法及一个简化的计算模型体系对这个膦酰化抑制反应进行理论研究.考虑了两种反应途径.PathA涉及FAAH的催化三联体的所有残基,是一个分步的加成-消除过程,形成两性离子的三角双锥中间体,其中第一步反应是决速步骤.在这个反应途径中,Ser217和Lys142对亲核试剂Ser241起到碱催化活化的作用,而Ser217充作Lys142和Ser241之间的桥梁.此外,溶剂中的一个水分子作为Lys142和MAFP间的＂氢桥＂具有关键的作用,通过给出和接收质子促进了长距离的质子转移.PathB是催化三联体中的残基Lys142被突变为丙氨酸以后的膦酰化反应,也是一个分步过程.水的本体溶剂效应通过极化连续介质模型（PCM）估算.计算结果显示膦酰化反应的PathA是优势途径,在水溶液中其决速步骤的活化能垒为64.9kJ·mol^-1.FAAH催化三联体中残基Lys142的变异会降低膦酰化反应的速率,这与实验结果相一致.

英文摘要：

Methyl arachidonyl fluorophosphonate （MAFP） is an inhibitor of the fatty acid amide hydrolase （FAAH）.We studied the phosphonylation reaction of the serine241 （Ser241）-serine217 （Ser217）-lysine142 （Lys142） catalytic triad of FAAH by MAFP, which leads to the loss of FAAH enzyme activity.This theoretical study was carried out by employing the B3LYP/6-311G（d,p） and MP2/6-311G（d,p） methods through a simplified model.Two reaction pathways were considered.Path A is a two-step addition-elimination process of the FAAH catalytic triad and the first step （addition process） is the rate-determining step and involves a zwitterionic trigonal bipyramidal intermediate.In this reaction pathway, both Ser217 and Lys142 in FAAH contribute to the base-catalyzed activation of the nucleophile Ser241 while Ser217 serves as a bridge between Lys142 and Ser241.In addition, one of the solvent water molecules performs a key role to act as a＂ hydrogen bridge＂ connecting the Lys142 residue and MAFP by donating and accepting protons to promote long-range proton transfer.Path B （after mutation of the Lys142 residue to alanine） is also a stepwise process.The bulk effect of water as a solvent was considered via the polarizable continuum model （PCM）.The obtained results show that for this phosphonylation reaction, Path A is the most favorable mechanism with an activation free energy barrier of 64.9 kJ·mol-1 in aqueous solution.We also conclude that the mutation of the FAAH catalytic triad at the Lys142 residue decreases the rate of phosphonylation.This is in good agreement with the experimental observations.