| DC 欄位 |
值 |
語言 |
| DC.contributor | 化學學系 | zh_TW |
| DC.creator | 石淵琪 | zh_TW |
| DC.creator | Yuan-ci Shih | en_US |
| dc.date.accessioned | 2011-7-26T07:39:07Z | |
| dc.date.available | 2011-7-26T07:39:07Z | |
| dc.date.issued | 2011 | |
| dc.identifier.uri | http://ir.lib.ncu.edu.tw:444/thesis/view_etd.asp?URN=982203036 | |
| dc.contributor.department | 化學學系 | zh_TW |
| DC.description | 國立中央大學 | zh_TW |
| DC.description | National Central University | en_US |
| dc.description.abstract | 本篇論文利用replica-exchange molecular dynamics配合implicit membrane Born model 模擬阿茲海默症的致病蛋白， Abeta (25-35)，序列置換對其在水-膜環境下組態的變化。Abeta(25-35) 是全長Abeta的部分區段，但Abeta(25-35) 保留全長Abeta的特性與毒性。有趣的是Abeta(35-25) 卻不具有毒性。先前觀點認為Abeta胜肽的疏水性越高則毒性可能越強。因此本篇研究Abeta(25-35) 氨基酸序列對其在水-膜環境的組態差異。研究的四條胜肽分別為Abeta(25-35)、Abeta(25-35) 序列相反的Abeta(35-25)、親疏水胺基酸交錯的胜肽 (Abeta(25-35)-Alt) 與疏水性N端的胜肽(Abeta(25-35)-Shuffled)。模擬結果顯示膜環境可以誘導helix結構的生成。Helix結構的長度及穩定度會影響胜肽分布在膜疏水核心及膜親水區域的比例，且這四條胜肽的摺疊與穿膜有不同的行為。綜合胜肽在膜環境的二級結構與位置的關係，Abeta(35-25)具有較穩定的helix結構且擴散較Abeta(25-35) 慢，這些特性可能會使得Abeta(35-25)有較低程度的聚集，可以解釋為何Abeta(35-25)在實驗上不具有毒性。
第二部分利用全原子模型模擬Abeta(25-35)、N27A-Abeta(25-35) 與 M35A-Abeta(25-35) 三條胜肽在膜環境的結構與計算胜肽在膜上的擴散係數。模擬結果顯示胜肽在膜環境的二級結構與擴散係數和毒性的關係，此外，模擬結果發現Abeta(25-35)可膜上形成beta-bridge，beta-bridge可能作為一個模板加速Abeta在膜上amyloid fibril的形成。了解Abeta在膜環境的構型提供一個新的觀點，可以了解結構與神經毒性的關連與藥物設計達到降低Abeta聚集。
| zh_TW |
| dc.description.abstract | The sequence effects of Alzheimer’s amyloid-beta fragment Abeta(25-35) on the configurations within membrane are investigated by replica-exchange molecular dynamics (MD) simulations with implicit membrane generalized Born model. Neurotoxicity of Abeta(25-35) is similar to the full length Abeta. Four peptides have same amino acids of Abeta(25-35), but with different sequences were simulated in a water-membrane environment. Although they have same amino acids, they have distinct configurations within membrane. Simulations show the membrane can induce the formation of helix structure. The helix length and stability of these four peptides are in the order of Abeta(25-35)-Shuffled > Abeta(35-25) > Abeta(25-35) > Abeta(25-35)-Alt. This order is in consistent with their fractions partitioned inside membrane’s hydrophobic core. These four peptides show different behaviors of interfacial folding and membrane insertion. The more structured and slower diffusion nature of Abeta(35-25) than those of Abeta(25-35) will lead to a lower degree of aggregation and consequently a lower neurotoxicity. This rationalization is in consistent with experimental results that Abeta(35-25) is nontoxic and vice versa. The second study employed all-atom long time-scale MD simulations to explore the configurations of Abeta(25-35), N27A-Abeta(25-35) and M35A-Abeta(25-35) aimed to rationalize their relative neurotoxicities. The relative neurotoxicities of these three peptides do not follow the general hydrophobicity-neurotoxicity relationships. We correlate their relative neurotoxicities with their relative mobilities and structures within membrane. This correlation is well rationalized by kinetics and thermodynamics. A stable beta-bridge structure of Abeta(25-35) is formed within membrane. We proposed this structure as a template in accelerating the amyloid formation within membrane. Understanding the configurations of Abeta peptides within membrane provides new insights to understand their neurotoxicities and give structure-based clues for rational drug design retarding amyloid aggregation.
| en_US |
| DC.subject | 胜肽 | zh_TW |
| DC.subject | 組態 | zh_TW |
| DC.subject | Amyloid-Beta | en_US |
| DC.subject | Abeta | en_US |
| DC.subject | configuration | en_US |
| DC.title | 類澱粉胜肽Abeta(25-35) 序列影響該類胜肽在水-膜環境下的組態: 強調多樣性的神經毒性 | zh_TW |
| dc.language.iso | zh-TW | zh-TW |
| DC.title | Sequence Effects of Amyloid-Beta (25-35) Peptides on the Configurations within Membrane: Highlight for Diverse Neurotoxicities | en_US |
| DC.type | 博碩士論文 | zh_TW |
| DC.type | thesis | en_US |
| DC.publisher | National Central University | en_US |