發(fā)布時(shí)間：2018-12-24 09:37

【摘要】：自由基是帶有未成對(duì)電子的分子、離子或基團(tuán),在體內(nèi)可以通過(guò)多種途徑產(chǎn)生。研究發(fā)現(xiàn)許多疾病,例如神經(jīng)退行性疾病以及機(jī)體的衰老等等與自由基有很大的關(guān)系。氨基酸在生物體內(nèi)由于廣泛的分布和較低的氧化還原電位,成為許多種自由基進(jìn)攻的靶標(biāo),其中甲硫氨酸是最容易氧化的氨基酸之一。甲硫氨酸的氧化不僅代表了一類重要的蛋白翻譯后修飾過(guò)程,也是衰老和許多疾病(如:阿爾茨海默氏癥、瘋牛病和帕金森氏癥等神經(jīng)退行性疾病)的誘因之一,因此甲硫氨酸的氧化機(jī)理目前已經(jīng)引起了廣泛的關(guān)注。研究甲硫氨酸模型肽的氧化機(jī)理對(duì)揭示神經(jīng)退行性疾病的發(fā)病機(jī)理,篩選相關(guān)治療藥物都有一定意義。 目前,許多實(shí)驗(yàn)方法已被用來(lái)探討氨基酸的氧化機(jī)制,其中脈沖輻解方法是最有力的手段之一。對(duì)氨基酸各氧化中間體瞬態(tài)吸收光譜的歸屬研究可以初步建立氨基酸的氧化“路線圖”。然而瞬態(tài)吸收譜的歸屬通常是有爭(zhēng)議的,因此不同的觀察者可能給出不同的甚至相互矛盾的結(jié)果。量子化學(xué)計(jì)算目前廣泛應(yīng)用于化學(xué)、生命科學(xué)、材料科學(xué)等領(lǐng)域的研究,是探討分子結(jié)構(gòu)-功能關(guān)系的重要研究手段之一,可以計(jì)算小分子幾乎所有的物理化學(xué)性質(zhì)。考慮到量子化學(xué)的密度泛函理論(DFT)方法,特別是含時(shí)DFT(TD-DFT)方法已被成功用于探討天然產(chǎn)物的氧化還原機(jī)制,我們采用了DFT方法對(duì)甲硫氨酸及其模型肽進(jìn)行了比較詳盡的理論研究。 首先,選擇小分子有機(jī)硫化合物二甲基硫和二乙醇基硫評(píng)價(jià)了計(jì)算方法的基組依賴性和長(zhǎng)程溶劑效應(yīng);其次,選擇HOO·-H_2O自由基評(píng)價(jià)了短程溶劑效應(yīng),即結(jié)合水的氫鍵對(duì)光譜的影響;最后,用經(jīng)過(guò)評(píng)價(jià)的DFT和TD-DFT方法,對(duì)甲硫氨酸模型肽N-乙酰甲硫氨酸氨基在水溶液中的脈沖輻解氧化過(guò)程進(jìn)行了詳盡的計(jì)算,不僅驗(yàn)證了實(shí)驗(yàn)提出的氧化機(jī)理,而且指出質(zhì)子化形式在甲硫氨酸模型肽的氧化反應(yīng)中應(yīng)予以考慮,這為進(jìn)一步的實(shí)驗(yàn)研究提供了啟發(fā)。此外,對(duì)甲硫氨酸亞砜的進(jìn)一步氧化機(jī)制也進(jìn)行了計(jì)算。 總之,通過(guò)對(duì)甲硫氨酸及其模型肽氧化機(jī)理的研究,證明DFT方法特別是TD-DFT方法可以作為氨基酸氧化機(jī)理實(shí)驗(yàn)研究的重要補(bǔ)充。 全文共分六章內(nèi)容:其中第一章為綜述部分,介紹了自由基損傷甲硫氨酸模型肽
[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.
【學(xué)位授予單位】：山東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2006
【分類號(hào)】：R363

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