博碩士論文 953204003 詳細資訊




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姓名 張育維(Yu-Wei Chang)  查詢紙本館藏   畢業系所 化學工程與材料工程學系
論文名稱 類澱粉胜肽聚集行為之電腦模擬
(Aggregation and Membrane Interactions of Amyloid b Peptides Fragments (16-22 & 25-35) in Water-Membrane Environment Studied by Molecular Dynamics Simulations)
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摘要(中) 本論文利用最新發展的implicit solvent/membrane模型,配合定溫分子動態法及變溫replica exchange分子動態法模擬Ab16-22及Ab25-35胜肽鏈在水相中及有膜存在的環境下,其聚集及吸附的機制,以期了解全長Ab1-40/42的細胞毒性機制。此ㄧ方法可改善全原子模型計算時間不足的問題,進而使模擬的時間尺度更能逼近實驗的條件,且藉由從原子及動態的時間角度出發,可彌補實驗上不易觀察到的現象。
由於Ab16-22(較具疏水性)與Ab25-35(兩性性質)基本性質不同,表現出的聚集及吸附行為也不同:Ab16-22胜肽鏈傾向於在水相中先行聚集而成寡聚物,而後再逐漸吸附到膜面上;然而,Ab25-35胜肽鏈傾向以單體的形態先吸附到膜面上,吸附上膜面的單體在膜面上互相聚集形成寡聚物;在水相中,Ab16-22胜肽鏈傾向形成b-sheet二級結構,Ab25-35胜肽鏈則傾向形成helix結構;在膜面上的結構與水相中不同,Ab16-22胜肽鏈在膜面上傾向形成helix,而Ab25-35胜肽鏈則表現出較多樣的結構形態,包含形成在C端的helix結構。雖然Ab16-22及Ab25-35兩者的聚集及吸附表現不同,但其聚集及吸附的主要交互作用力卻相似:兩者聚集主要是以疏水作用力為主,而寡聚物吸附到膜面上則是以靜電作用力為主。
本研究從原子尺度了解Ab的聚集及吸附的機制,可提供我們一個理論基礎,以合理設計相關的治療藥物,以抑制Ab細胞毒性的產生。
摘要(英) This study employed the constant temperature molecular dynamics and replica-exchange molecular dynamics in terms of the recently developed implicit solvent and membrane models to simulate the aggregation and adsorption mechanisms of the Ab16-22 and Ab25-35 peptide in the present of membrane. This study is motivated to understand the toxic mechanism of full-length Ab1-40/1-42. Our method improves the time-consuming problem of all-atom simulations and will approach the experimental time scale. In views of atomic and fast time scales, our results complement the intermediate processes which were difficult to be observed experimentally.
Due to the different properties of Ab16-22 and Ab25-35 peptides in which they are hydrophobic and amphiphilic, respectively, their mechanisms of aggregation and adsorption are also different: Ab16-22 peptides are prone to aggregate in water phase, and then to be adsorbed to membrane; In contrast, Ab25-35 peptides trends to be adsorbed on membrane in the monomer form, then, the monomers are to be aggregated on membrane. In water phase, Ab16-22 peptides prefer to form b-sheet secondary structure and the Ab25-35 peptides form helix secondary structure. In membrane phase, Ab16-22 peptides prefer to form helix secondary structure. The secondary structures of Ab25-35 peptides in membrane are more diverse. If the helix secondary structure of Ab25-35 peptides is formed, it exists in the C-terminal. Although the aggregation and adsorption mechanisms are different for Ab16-22 and Ab25-35 peptides, they shares similar interactions: For aggregation, the interactions are mainly dominated by hydrophobic effect; for adsorption, it is driven by electrostatics interactions.
This study understands the mechanisms of Ab aggregation and adsorption in atomic and fast time scales proving us a theoretical guideline for rational drug design to inhibit the cell toxicity of amyloid.
關鍵字(中) ★ 分子動態模擬
★ 類澱粉胜肽
關鍵字(英) ★ molecular dynamics simulations
★ beta amyloid
論文目次 中文摘要 I
Abstract II
目錄 III
圖目錄 V
表目錄 X
第一章 序論 1
第二章 文獻回顧 2
2.1 前言 2
2.2 蛋白質的摺疊之原理及機制 3
2.3 蛋白質錯誤摺疊、聚集及類澱粉蛋白纖維之生成 5
2.4 阿茲海默症(Alzheimer’s Disease,AD) 7
2.5 類澱粉胜肽(b-Amyloid,Ab) 9
2.6 類澱粉胜肽纖維分子結構 10
2.6.1 固態核磁共振 11
2.6.2 電子自旋共振(EPR) 13
2.6.3 X-Ray散射 13
2.7 類澱粉胜肽纖維形成之巨觀機制 14
2.8 分子動態法模擬類澱粉胜肽之聚集 15
第三章 方法與原理 18
3.1 簡介 18
3.2 分子力場(Force Field) 19
3.2.1 鍵伸縮位能 20
3.2.2 鍵彎曲位能 20
3.2.3 鍵角扭曲位能 21
3.2.4 不規則鍵角扭曲位能 21
3.2.5 凡得瓦作用力 22
3.2.6 庫倫靜電作用力 23
3.3 基本動力原理 24
3.4 週期性邊界條件(Periodic Boundary Conditions, PBC) 25
3.5 Generalized Born Solvent Model (GB Model) 27
3.6 Replica-Exchange Molecular Dynamics Method (REMD) 31
3.7 Dictionary of Secondary Structure of Proteins (DSSP) 37
3.8 分子動態模擬系統與條件、方法介紹 40
3.8.1 主要模擬分子 41
3.8.2 系統概述: 41
第四章 結果與討論 43
4.1 Ab16-22聚集及吸附行為的探討 44
4.1.1 Ab16-22胜肽鏈與膜的交互作用機制 44
4.1.2 Ab16-22在水相中的聚集 84
4.2 Ab25-35聚集及吸附行為的探討 91
4.2.1 Ab25-35胜肽鏈聚集及吸附到膜面的機制 91
4.2.2 Ab25-35胜肽鏈的二級結構 112
4.2.3 Ab25-35在水相中的聚集 123
第五章 結論 127
第六章 參考文獻 129
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指導教授 陳文逸(Wen-Yih Chen) 審核日期 2008-7-22
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