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研究生:林良俊
研究生(外文):Liang-Chun Lin
論文名稱:類澱粉乙型胜肽前驅蛋白穿膜區在脂環境下的結構模擬
論文名稱(外文):Structural simulation of Aβ60 in lipid environment
指導教授:林達顯
指導教授(外文):Ta-Hsien Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物醫學資訊研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:65
中文關鍵詞:阿滋海默症類澱粉蛋白分子動態模擬
外文關鍵詞:Alzheimer's diseaseMD simulation
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阿滋海默症(Alzheimer’s disease, AD)即是俗稱的老年失智症,它是一種不可逆的神經退化性疾病,能引發漸進性失智及神經元壞死。造成阿滋海默症的確切機制仍然不明,1992年Hardy 和 Higgins 提出了amyloid hypothesis,指出Aβ形成的癍塊是造成阿滋海默症最主要的成因。在阿滋海默症病患的腦部有兩個主要的組織病理表徵,分別為在大腦皮質內產生之老化癍塊(senile plaque)及在神經細胞內產生之神經微纖維糾結(neurofibrillary tangles)。而老化癍塊中的主要成分為一種疏水性的胜肽名為��-類澱粉胜肽(β-amyloid peptide, Aβ),此胜肽是一種較大的跨膜蛋白質叫β-類澱粉前趨蛋(β-amyloid precursor protein; APP)的蛋白水解產物,其主要有兩種異構物分別為含有40及42個胺基酸。β-類澱粉胜肽為可溶性胜肽,血液及腦脊髓液可測得其含量,然而它在特定的環境下會以極慢的速率發生分子凝集(aggregation),此凝集作用將單分子可溶之β-類澱粉胜肽轉變成不可溶的微纖維(protofibril),繼而沉積為類澱粉癍塊。研究顯示,β-類澱粉胜肽在凝結狀態下具有神經毒性。因此,了解凝集過程的分子機轉將有助於微纖維生成抑制劑之設計及開發。Aβ 如何由單一分子群聚,最後纖維化形成癍塊,此過程之分子機制仍尚未明朗。目前一般認為,β-類澱粉胜肽的初始結構為α-螺旋狀(α-helix)其後結構轉變為不定型(random coil)再進一步轉變為β-摺板(β-strand)。在��-摺板型的階段中,胜肽間便開始互相聚集最後形成巨大的聚合物,這就是神經細胞外的老年斑。Aβ在細胞膜中的結構仍然是未知的,若能獲得其在細胞膜中的結構資訊,將有助於我們了解Aβ凝集作用之分子機制。本研究利用分子動態模擬的方式獲得Aβ在細胞膜中的結構資訊,探討Aβ在離開細胞膜前的結構及它在細胞膜中的穩定度,另外與家族變異型Arctic(E22G)做一比較。結果發現Arctic 變異型氮端在水的部分的結構比一般型更快變成不定型且更快浮到細胞膜表面,此結果暗示Aβ在細胞膜即可能開始進行聚集及退化。
Alzheimer’s disease (AD) is a neurodegenerative disease which leads to progressive dementia and neuronal death. Currently, the molecular pathogenesis of this disease is still not yet clear. The main histopathological hallmarks of AD are the senile plaques within the cerebral cortex and the neurofibrillary tangles within the nerve cells. The primary component of senile plaques is β-amyloid peptide (Aβ), which is derived from proteolysis of a much larger membrane-spanning protein known as β-amyloid precursor protein (APP). Aβ has two major isoforms, Aβ40 and Aβ42, containing 40 and 42 residues, respectively. Aβ is a soluble peptide which can be detected in blood and cerebrospinal fluid. However, it will polymerize at a slow rate under certain environmental condition. Recent studies have suggested that Aβ has neurotoxic properties in an aggregated state. Thus, knowing the molecular mechanism of the aggregation process of Aβ may facilitate the design and development of fibrillogenesis inhibitors.
From the structural point of view, the aggregation process involves conformational changes and self-assembly of Aβ. The initial structural information of Aβ in membrane may help us gain more insight into the molecular mechanism of Aβ aggregation. In this study, we applied molecular dynamics simulation to obtain the structural information of Aβ40 in membrane. Moreover, we also performed the structural simulation on Arctic mutant (Aβ40 (E22G)). Our results showed that the structure of the N-terminal domain of Aβ40(E22G) melt into random coil faster than wild-type Aβ40. Besides, the Arctic mutant is more prone to floating to the surface of membrane than wild-type Aβ40. These results suggest that both wild-type Aβ40 and Aβ40(E22G) are unstable in the membrane environment, and the unfolding and aggregation process may occur in the membrane.
中文摘要 Ⅰ
英文摘要 Ⅱ
目錄 Ⅲ
圖目錄 Ⅳ
第一章、序論 1
第二章、研究方法與材料 5
2.1 �n分子動態模擬系統之建構 5
2.2 分子動態模擬 6
2.3 數據分析 7
2.3.1 二級結構時間演化圖及��-helix統計分析 9
2.3.2 胺基酸垂直移動圖 10
第三章、 結果 11
3.1 A��60在DMPC bilayer中的結構 11
3.1.1 野生型A�����~�n的結構 11
3.1.2 Arctic家族變異型A��60(E22G)的結構 11
3.2 比較野生型A��60與A��60(E22G)的結構 12
3.3 A��60起始位置對結構的影響 13
3.4 A��40在DMPC bilayer中的結構 14
第四章、討論 15
文獻參考 17
附件一、利用Gromacs跑分子動態模擬之流程 43
附件二、刪除膜中水分子程式java原始碼 46
附件三、數據分析工具程式C++原始碼 50
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