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系統識別號 U0026-0812200915385264
論文名稱(中文) 利用分子動力學研究糊蛋白多聚體之聚集現象
論文名稱(英文) Investigating of the structural characteristics and aggregation of amyloid beta oligomer using molecular dynamics simulation
校院名稱 成功大學
系所名稱(中) 工程科學系碩博士班
系所名稱(英) Department of Engineering Science
學年度 97
學期 2
出版年 98
研究生(中文) 池國維
研究生(英文) Kuo-Wei Chih
電子信箱 n9696437@ccmail.ncku.edu.tw
學號 n9696437
學位類別 碩士
語文別 中文
論文頁數 96頁
口試委員 指導教授-黃吉川
口試委員-陳顯禎
口試委員-王雲哲
口試委員-郭余民
口試委員-楊瑞珍
中文關鍵字 多聚體  聚集  分子動力學  貝它糊蛋白 
英文關鍵字 amyloid beta  molecular dynamics  oligomers  aggregation 
學科別分類
中文摘要 本文研究amyloid beta (Aβ)分子,其C端修飾後,所造成的影響。而許多文獻證實,這類分子是造成阿茲海默症的原因之一。而這個由39-42個胺基酸所組成的Aβ胜肽分子,會經由聚集的方式形成斑塊(plaque),進而阻斷腦部神經的傳遞。因此Aβ聚集過程的研究,對於治療阿茲海默症來說,便顯得相當重要。目前經由原子力顯微鏡(atom force microscopy)所觀察到的現象,發現Aβ在形成纖維狀結構前,Aβ單體會先以多聚體模式聚集成球狀物。因此本論文的重點便是利用分子動力學方法來研究Aβ的原型(wild-type)與其相似物(analogues)在聚集過程中,其結構的穩定性與可能發生的聚集行為。詳細的研究內容如下所示。(1)原型Aβ17-42五聚體。模擬結果顯示其會相互聚進而形成一個穩定的球狀物分子、(2)原型Aβ17-42五聚體中的第41個具有疏水性的異白胺酸(Isoleucine;Ile)殘基皆置換為具有親水性的天冬醯胺(Asparagine;Asn)。結果發現其C端的疏水核心距離有縮小的趨勢;接著,原型Aβ17-42五聚體中的第41個具有疏水性的Ile殘基皆置換為鹼性的精胺酸(Arginine;Arg)。結果顯示其整體五聚體的鹽橋作用力出現的次數相較於原型的Aβ17-42五聚體來的多,但在扭轉半徑的分析方面卻無太大的差異、(3) 同時截斷原型Aβ17-42五聚體其C端的第41與第42個殘基,即Aβ17-40五聚體。結果顯示當五條單體皆截去位於第41與第42個殘基後,整體穩定度較不如截去前穩定,並且表現出較高的扭轉半徑值;僅截斷原型Aβ17-42五聚體其C端的第42個殘基,即Aβ17-41五聚體。結果顯示在二級結構的含量上與截去前的分布類似,含有約50%以下的coil和20%左右的β-sheet,且整體分子的扭轉半徑值有變小的現象、(4) 原型Aβ1-42五聚體。模擬結果發現,聚集後的扭轉半徑有類似前人所提到的趨勢,但在二級結構的分析部份,發現一樣具有高比例的coil結構,但β-sheet的比例卻降低了。上述研究所得到的重要結果,將對阿茲海默症的病理機制提供一個更深入的了解。
英文摘要 At present there are considerable literatures indicated that amyloid-β (Aβ) peptides play a major critical role caused the Alzheimer’s disease (AD). The Aβ is a 39 to 43 amino acid peptide that is a major component in the senile plaques of AD. These monomer Aβ peptides could aggregate the plaque form and further hinder the nervous transmission. Thus, the aggregation behavior of Aβ peptides is a rather significant event for treating the AD. On the other hand, from the atom force microscopy (AFM) observations, the monomer Aβ peptides form the sphere oligomers before they form the amyloid fibrils. Motivated by these findings, at present study attempts to investigate the structural stability and possible aggregation behavior including the wild-type and it’s analogues of Aβ oligomers using molecular dynamics (MD) simulations. The detailed study contents are as follows: (1) Wild-type Aβ17-42 pentamer. The simulated results reveal that the pentamer aggregating the stable sphere form; (2) Ile41-to-Asn mutation within the coding sequence of wild-type Aβ17-42 pentamer disrupts the hydrophobic core. That is, C-terminus forms relatively weak hydrophobic interaction, as reflected by the hydrophilic residue 41Asn. As a result, residue 41Asn tends to close with residue 34-36; subsequently, the case of Ile41-to-Arg mutation was also studied. Our results indicate the appearance of salt bridge was increased with mutations than wild-type Aβ17-42. Besides, the radius of gyration (Rg) was also examined. The results display that the Rg value exhibit the same tendency between mutation and wild-type Aβ17-42; (3) The absence of residue 41-42 destabilize the conformation in wild-type Aβ17-42 pentamer because of the lack of the hydrophobic interaction in C-terminus; However, the absence of residue 42 in wild-type Aβ17-42 pentamer enhance aggregation. This result is supported by the same distribution of secondary structure with wild-type, but smaller value for Rg. (4) Because of the structural heterogeneity in N-terminus of Aβ, the exact structure of Aβ oligomer is still incomplete. Here we performed MD simulation to investigate the formation of Aβ1-42 pentamer. The results show that the distribution of secondary structure in this case differs from the case of N-terminus truncated pentamer as mentioned above.
論文目次 中文摘要 I
Abstract II
致謝 III
目 錄 IV
表目錄 VII
圖目錄 VIII
符號表 X
第一章 緒 論 1
1.1前言與背景 1
1.2文獻回顧 6
1.3研究動機與目的 13
第二章 模擬方法與分析之設定 15
2.1 PDB檔之簡介 15
2.2 初始條件設定 19
2.3 模擬設備與其他相關軟體 22
2.4 分子動力學概論 23
2.5 GROMACS模擬流程 27
2.6 模擬相關經驗紀錄 32
2.6.1 pdb結構檔的殘基置換與修剪 32
2.6.2 模擬工作的續跑、延伸模擬時間 32
2.6.3 模擬中斷時,座標檔的提取與軌跡檔修剪 34
2.7 作用力定義及相關分析 39
2.7.1 鹽橋(salt-bridge)的定義 39
2.7.2 氫鍵(hydrogen bond)的定義 39
2.7.3 迴轉半徑(radius of gyration)的定義 39
2.7.4 二級結構(Secondary Structure)的定義 40
第三章 結果與討論 42
3.1 穩定度分析 42
3.1.1 Aβ17-42之五聚體 42
3.1.2 C端替換之Aβ17-42五聚體 45
3.1.3 C端截斷之Aβ17-42五聚體 53
3.1.4 Aβ1-42五聚體 59
3.2 二級結構分析 61
3.2.1 Aβ17-42之五聚體 61
3.2.2 C端替換之Aβ17-42五聚體 64
3.2.3 C端截斷之Aβ17-42五聚體 69
3.2.4 Aβ1-42之五聚體 73
第四章 原絲纖維 76
第五章 結 論 79
第六章 未來展望與建議 84
參考文獻 85
附錄A 各項參數設定 90
自述 96
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