诚信声明我声明，所呈交的毕业论文（设计）是本人在老师指导下进行的研究工作及取得的研究成果。据我查证，除了文中特别加以标注和致谢的地方外，论文(设计)中不包含其他人已经发表或撰写过的研究成果，也不包含为获得其他教育机构的学位或证书而使用过的材料。我承诺，论文（设计）中的所有内容均真实、可信。毕业论文（设计）作者（签名）：年月日FAK共价抑制剂选择性的计算研究【摘要】目的：研究具有相同共价弹头的共价抑制剂EUW与EUQ与FAK共价结合能力的巨大差异背后电子结构层面的原因，从而指导靶向半胱氨酸的共价抑制剂涉及与机理研究。方法：使用量子化学方法结合半经验方法对共价抑制剂EUW/EUQ的本底反应性进行建模，并基于机器学习预测、双分子模型计算以及概念密度泛函描述符等对其反应性进行定量化评估。使用簇模型结合范围分离泛函oB97XD在oB97XD/(ma-)def2svp/CPCM(H2O)级别下对反应历程中涉及的底物、中间体、过渡态与产物进行优化与搜寻，得到相关热动力学参数，比较差异。并且在B3LYP-D3/def2-TZVP/CPCM(H2O)级别下使用元动力学方法研究水介导质子转移过程中的自由能变化。结果：机器学习预测、双分子模型的能垒计算以及概念密度泛函描述符均表明EUW在共价弹头受到进攻位点处具有比EUQ更高的本底亲电性，从而使得EUW更容易受到残基CYS427的巯基的进攻。对簇模型计算同样表明EUQ受到CYS427进攻所需的能垒远远高于EUW,且EUW的硫-迈克尔加成基元反应步骤出现负能垒现象，表明该反应速度极快且远远快于EUQ对应的反应。对计算级别无法找到过渡态的质子转移过程，元从头算动力学计算证明其在B3LYP-D3/def2-TZVP/CPCM(HzO)级别下存在一阶鞍点，且具有很低的反应能垒。结论：①共价抑制剂EUQ本底反应性远低于EUW②共价抑制剂EUQ共价结合过程的能垒远高于EUW。【关键词】黏着斑激酶：共价抑制剂：簇模型：密度泛函理论：概念密度泛函：元从头算动力学Computational Study On the Selectivity of FAKCovalent Inhibitors[Abstract]Objective:The main purpose of this study is to find a rationalebehind the tremendous reactivity difference towards the process of covalent linkage toFAK between covalent inhibitors EUW and EUQ at the electronic-structure level,andproffer possible instructions for the future design/development of new covalent inhibitors and enlightening insight into the understanding of their mechanisms.Methods:Several diverse quantum chemical and semi-empirical methods are employed to investigate the inherent reactivity of covalent inhibitors EUW/EUQ.Quantitative methodologies including online machine-learning-based platform,two-molecule models and conceptual density functional indices are utilized to examine the electrophilicity difference at the covalent warhead,while QM-Cluster methodology combined with the range-separated fuctional B97XD is implemented to obtain all the stable structures along the reaction path involving reactants,intermediates,transition states and the product aswell as the thermodynamic and kinetic properties at B97XD/(ma-)def2svp/CPCM(H2O)level.To study the proton transfer process which defies the identification atB97XD/(ma-)def2svp/CPCM(H2O)level,ab initio dynamics with metadynamics is applied to probe its free energy change.Results:Considerable electrophilicty differenceat the terminal carbon of the covalent warhead is found between EUW and EUQ during the reactivity analysis,making EUW more subject towards the nucleophilic attackof the CYS427 residue on FAK.Moreover,the barrier of the covalent attack elementary reaction manifests itself much higher for EUQ than EUW,which is consistent withthe CDFT results.And in the metadynamics of the proton transfer reaction,a first-order saddle point is shown on the 2D free energy map and gives a very low barrier.Conclusion:Two explanations could be made according to the computation results:1Inherently EUQ is less reactive at the warhead site 2 The barrier of the covalent linkage process for EUQ is much higher.