本文關(guān)鍵詞： 蛋白質(zhì)構(gòu)象病 α-突觸核蛋白 錯(cuò)誤折疊 聚集 突變 分子動(dòng)力學(xué)模擬　出處：《蘭州大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：蛋白質(zhì)聚集是一個(gè)高度復(fù)雜的過(guò)程并伴隨出現(xiàn)不同結(jié)構(gòu)和形態(tài)的聚合物,其會(huì)形成淀粉樣沉淀從而引起蛋白質(zhì)構(gòu)象病(protein conformational diseases),包括帕金森病、Ⅱ-型糖尿病和亨廷頓氏舞蹈病等。蛋白質(zhì)發(fā)生錯(cuò)誤折疊會(huì)在很大程度上影響其正常的生物學(xué)功能,因而也被認(rèn)為是神經(jīng)退行性疾病的主要原因。因此,充分理解這些疾病相關(guān)蛋白的錯(cuò)誤折疊和聚集機(jī)理及由此引發(fā)的生理效應(yīng)是研究聚集過(guò)程與細(xì)胞毒性之間聯(lián)系的關(guān)鍵,也是靶向藥物設(shè)計(jì)和開(kāi)發(fā)的重要前提。分子動(dòng)力學(xué)(molecular dynamics,MD)模擬方法作為計(jì)算機(jī)輔助手段可以和現(xiàn)有實(shí)驗(yàn)手段很好的互補(bǔ),克服了傳統(tǒng)實(shí)驗(yàn)研究中的局限性,進(jìn)而從原子水平上認(rèn)識(shí)淀粉樣沉淀的形成過(guò)程。在對(duì)特定蛋白質(zhì)的錯(cuò)誤折疊和聚集的研究過(guò)程中,運(yùn)用計(jì)算機(jī)模擬的方法可以獲取到實(shí)驗(yàn)中無(wú)法獲取的有效信息。在本論文中,我們應(yīng)用常規(guī)分子動(dòng)力學(xué)模擬和副本交換動(dòng)力學(xué)模擬方法對(duì)帕金森癥特定蛋白質(zhì)(α-突觸核蛋白)的折疊和聚集過(guò)程展開(kāi)了研究,論文內(nèi)容分為以下四個(gè)部分:第一部分主要對(duì)神經(jīng)退行性疾病與蛋白質(zhì)錯(cuò)誤折疊之間的關(guān)系進(jìn)行了闡述,接著說(shuō)明了神經(jīng)退行性疾病相關(guān)蛋白發(fā)生錯(cuò)誤折疊與聚集的機(jī)制及藥物設(shè)計(jì)的思路,并重點(diǎn)關(guān)注α-突觸核蛋白的致病機(jī)制與帕金森癥之間的聯(lián)系;最后對(duì)本論文用到的分子動(dòng)力學(xué)模擬方法的原理與流程步驟進(jìn)行了詳細(xì)闡述。第二部分中,我們基于副本交換的分子動(dòng)力學(xué)模擬研究了A53T突變對(duì)α-synuclein 47-56序列折疊的影響,對(duì)野生型與突變型短肽分別進(jìn)行了200 ns的REMD模擬。通過(guò)對(duì)二級(jí)結(jié)構(gòu)含量的測(cè)定、構(gòu)象空間特征的比較及溶劑可及化表面積的分布的分析,我們發(fā)現(xiàn)A53T突變較野生型有較大的可能來(lái)轉(zhuǎn)化成β-sheet結(jié)構(gòu)來(lái)增強(qiáng)蛋白質(zhì)發(fā)生聚集的趨勢(shì)。第三部分主要內(nèi)容是基于分子動(dòng)力學(xué)模擬方法來(lái)研究A53T突變對(duì)α-突觸核蛋白46-97五聚體折疊和聚集的影響。我們對(duì)野生型與突變型-突觸核蛋白46-97多肽分別進(jìn)行了400 ns的分子動(dòng)力學(xué)模擬,結(jié)果表明野生型與突變型二級(jí)結(jié)構(gòu)均發(fā)生了改變,A53T突變的確使得五聚體有向β-sheet結(jié)構(gòu)轉(zhuǎn)變的趨勢(shì),使得整體結(jié)構(gòu)更加穩(wěn)定有利于蛋白質(zhì)的聚集。這是由于該突變影響到了整個(gè)體系的能量發(fā)生了變化,有利于五聚體向更穩(wěn)定的結(jié)構(gòu)轉(zhuǎn)變。A53T突變會(huì)影響到自身的折疊,進(jìn)一步會(huì)影響到五聚體的聚集。第四部分研究的是結(jié)合分子動(dòng)力學(xué)模擬來(lái)觀察以α-突觸核蛋白46-97五聚體為模板誘導(dǎo)核心肽段低聚化的過(guò)程。根據(jù)野生型與A53T突變型兩組分別誘導(dǎo)其對(duì)應(yīng)的短肽,通過(guò)200 ns的模擬過(guò)程總結(jié)出突變型作為模板誘導(dǎo)的效率較高,并且在五聚體的兩側(cè)單體都有明顯的β-sheet結(jié)構(gòu)形成,而對(duì)應(yīng)的野生型則只在一側(cè)的臨近單體出現(xiàn)了β-sheet結(jié)構(gòu)并且誘導(dǎo)效率較低。研究結(jié)果表明A53T突變有助于聚集,使α-突觸核蛋白結(jié)構(gòu)發(fā)生改變從而引起病癥的發(fā)生。本論文中,我們對(duì)A53T特定突變對(duì)α-突觸核蛋白錯(cuò)誤折疊和聚集的影響進(jìn)行了系統(tǒng)的分子動(dòng)力學(xué)模擬研究,所得結(jié)果可以從原子水平上更好地理解A53T突變型α-突觸核蛋白錯(cuò)誤折疊和聚集的機(jī)理,理解帕金森癥的致病機(jī)理與靶向藥物的設(shè)計(jì)研究提供理論基礎(chǔ)。
[Abstract]:Protein aggregation is a highly complex process with different structure and morphology of the polymer, the formation of amyloid deposition can cause protein conformational disease (protein conformational diseases), including Parkinson's disease, type 2 diabetes and Huntington's disease. Protein misfolding may affect its normal biological function in large degree, which was also thought to be a major cause of neurodegenerative disease. Therefore, to fully understand the physiological effects of these diseases related to protein misfolding and aggregation mechanism and the key link between research aggregation process and cell toxicity, an important prerequisite to drug design and development is also the target of molecular dynamics (molecular dynamics. MD), simulation method as computer aided method and the existing experimental methods can complement each other well, to overcome the traditional experimental study The limitations, and then from the atomic level understanding of amyloid formation process. In the course of the study on the aggregation of misfolded proteins and the specific, effective information using the computer simulation method can get the experiment can not be obtained. In this paper, we apply the conventional molecular dynamics simulation and Parkinson simulation method to copy disease specific protein dynamics exchange (alpha synuclein) folding and aggregation process is studied. The thesis is divided into the following four parts: the first part is mainly about the relationship between neurodegenerative diseases and protein folding errors are discussed, and then explains the neurodegenerative diseases associated with protein misfolding and aggregation the mechanism and drug design ideas, and focus on the pathogenesis of Parkinson's disease and between alpha synuclein links; at the end of this paper to use The molecular dynamics simulation principle and process method are discussed in detail. In the second part, we replica exchange molecular dynamics simulation research based on the effect of A53T mutation on fold alpha -synuclein 47-56 sequence, the wild type and mutant peptides were 200 ns REMD simulation. Through the determination of the content of two level structure the comparison of the characteristics of space and solvent conformation analysis and surface area distribution, we found that A53T mutant compared to the wild type are more likely to convert to the beta -sheet structure to enhance protein aggregation trend. The third part is the molecular dynamics simulation method based on A53T to study the effects of mutations on alpha synuclein 46-97 five mer protein folding and aggregation. The wild type and mutant - synuclein 46-97 polypeptides were 400 ns molecular dynamics simulations. The results show that Wild type and mutant two structures are changed, it makes the A53T mutant dimer has five changes to the beta -sheet structure of the trend, make the whole system more conducive to the stability of protein aggregation. This is due to the mutations affect the energy of the whole system changes, is conducive to the dimer structure to five stable transformation of.A53T mutation affects its own folding, further will affect five dimer accumulation. The fourth part of the study is to observe the alpha synuclein 46-97 five mer peptides as templates to induce the core process of oligomerization. Using the molecular dynamics simulation based on the wild type and A53T mutant groups were two induction of the corresponding peptide, through simulating the process of 200 ns summed up the high efficiency mutant as template to induce the monomer and dimer, both sides in the five have formed beta -sheet structure, and the corresponding wild type Only in the near side of the monomer structure induced by beta -sheet and low efficiency. The results show that A53T mutations contribute to the aggregation of alpha synuclein structural changes caused by the occurrence of the disease. In this paper, we carried out molecular dynamics simulation system of A53T specific mutations affecting misfolding the alpha synuclein aggregation and fault, the results from the atomic level to better understand the mechanism of aggregation of A53T mutant alpha synuclein misfolding and the pathogenesis of Parkinson's disease and target understanding and provide a theoretical basis to the design of drugs.

【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R742.5

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