甲硫氨酸模型肽自由基损伤机理的量子化学计算研究

发布时间：2018-12-24 09:37

【摘要】：自由基是带有未成对电子的分子、离子或基团,在体内可以通过多种途径产生。研究发现许多疾病,例如神经退行性疾病以及机体的衰老等等与自由基有很大的关系。氨基酸在生物体内由于广泛的分布和较低的氧化还原电位,成为许多种自由基进攻的靶标,其中甲硫氨酸是最容易氧化的氨基酸之一。甲硫氨酸的氧化不仅代表了一类重要的蛋白翻译后修饰过程,也是衰老和许多疾病(如:阿尔茨海默氏症、疯牛病和帕金森氏症等神经退行性疾病)的诱因之一,因此甲硫氨酸的氧化机理目前已经引起了广泛的关注。研究甲硫氨酸模型肽的氧化机理对揭示神经退行性疾病的发病机理,筛选相关治疗药物都有一定意义。目前,许多实验方法已被用来探讨氨基酸的氧化机制,其中脉冲辐解方法是最有力的手段之一。对氨基酸各氧化中间体瞬态吸收光谱的归属研究可以初步建立氨基酸的氧化“路线图”。然而瞬态吸收谱的归属通常是有争议的,因此不同的观察者可能给出不同的甚至相互矛盾的结果。量子化学计算目前广泛应用于化学、生命科学、材料科学等领域的研究,是探讨分子结构-功能关系的重要研究手段之一,可以计算小分子几乎所有的物理化学性质。考虑到量子化学的密度泛函理论(DFT)方法,特别是含时DFT(TD-DFT)方法已被成功用于探讨天然产物的氧化还原机制,我们采用了DFT方法对甲硫氨酸及其模型肽进行了比较详尽的理论研究。首先,选择小分子有机硫化合物二甲基硫和二乙醇基硫评价了计算方法的基组依赖性和长程溶剂效应;其次,选择HOO·-H_2O自由基评价了短程溶剂效应,即结合水的氢键对光谱的影响;最后,用经过评价的DFT和TD-DFT方法,对甲硫氨酸模型肽N-乙酰甲硫氨酸氨基在水溶液中的脉冲辐解氧化过程进行了详尽的计算,不仅验证了实验提出的氧化机理,而且指出质子化形式在甲硫氨酸模型肽的氧化反应中应予以考虑,这为进一步的实验研究提供了启发。此外,对甲硫氨酸亚砜的进一步氧化机制也进行了计算。总之,通过对甲硫氨酸及其模型肽氧化机理的研究,证明DFT方法特别是TD-DFT方法可以作为氨基酸氧化机理实验研究的重要补充。全文共分六章内容:其中第一章为综述部分,介绍了自由基损伤甲硫氨酸模型肽
[Abstract]:Free radicals are molecules, ions, or groups with unpaired electrons that can be produced in the body in a variety of ways. Many diseases, such as neurodegenerative diseases and aging, have been found to be associated with free radicals. Due to its wide distribution and low redox potential, amino acids have become the targets of many kinds of free radical attacks, among which methionine is one of the most easily oxidized amino acids. The oxidation of methionine not only represents an important process of post-translational modification of proteins, but also contributes to aging and many diseases, such as Alzheimer's disease, mad cow disease, Parkinson's disease and other neurodegenerative diseases. Therefore, the oxidation mechanism of methionine has attracted wide attention. It is important to study the oxidation mechanism of methionine model peptide in order to reveal the pathogenesis of neurodegenerative diseases and to screen related therapeutic drugs. At present, many experimental methods have been used to study the oxidation mechanism of amino acids, among which the pulse radiolysis method is one of the most powerful methods. The study on the transient absorption spectra of amino acid intermediates can establish the "road map" of amino acid oxidation. However, the attribution of transient absorption spectra is usually controversial, so different observers may give different or even contradictory results. Quantum chemistry calculation is widely used in the fields of chemistry, life science, material science and so on. It is one of the important means to study the structure-functional relationship of molecules. It can calculate almost all physical and chemical properties of small molecules. Considering that the density functional theory (DFT) method of quantum chemistry, especially the time-dependent DFT (TD-DFT) method, has been successfully used to study the redox mechanism of natural products, We used DFT method to study methionine and its model peptide in detail. Firstly, the base group dependence and long range solvent effect of the calculation method were evaluated by selecting the small molecule organic sulfur compounds, dimethyl sulfur and diethylsulfide. Secondly, HOO H 2O free radical was selected to evaluate the effect of short range solvent, that is, the effect of hydrogen bond of water on the spectrum. Finally, the pulse radiolysis oxidation process of methionine model peptide N-acetylmethionine in aqueous solution was calculated by DFT and TD-DFT methods, which not only verified the oxidation mechanism proposed in the experiment, but also confirmed the oxidation mechanism of the model peptide N-acetylmethionine in aqueous solution. It is also pointed out that the protonation form should be considered in the oxidation of methionine model peptide, which provides inspiration for further experimental study. In addition, the further oxidation mechanism of methionine sulfoxide was also calculated. In conclusion, by studying the oxidation mechanism of methionine and its model peptide, it is proved that the DFT method, especially the TD-DFT method, can be used as an important supplement to the experimental study on the oxidation mechanism of amino acids. This paper is divided into six chapters: the first chapter is the summary part, which introduces the free radical damage methionine model peptide.
【学位授予单位】：山东师范大学
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R363

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