以分子動態模擬探討來自Aβ上GVVIA和MVGGVV寡聚體的結構穩定性和聚集特性

Molecular Dynamics Simulations to Investigate the Structural Stability and Aggregation Behavior of the GGVVIA and MVGGVV Oligomers Derived from Amyloid β Peptide

張量凱(Liang-Kai Chang)

指導教授 ： 劉宣良

國立臺北科技大學/工程學院/生物科技研究所/碩士(2009年)

摘要

許多神經退化性疾病，例如阿茲海默症、帕金森氏症和亨丁頓舞蹈症都是由不同的胜肽聚集成纖維所造成。最近研究已將位於Aβ胜肽C端疏水區域的GGVVIA和MVGGVV的結構解出，且發現在兩個摺板間會緊密的互補而形成無水介面，稱之為“立體拉鍊“。在本文中，利用不同組別的分子動態模擬，於水的環境中研究不同大小規模的GGVVIA和MVGGVV寡聚體的結構穩定性和聚集特性。在GGVVIA和MVGGVV寡聚體的實驗結果顯示，隨著組別中β-strand的增加，也會造成結構穩定性的增加。接著比較SH1模型和SH2模型的差異，雙層β-sheet模型的結構穩定性高於單層β-sheet模型，這項結果指出多了額外的β-sheet在維持結構的穩定性是必要的。我們進一步推測SH2-ST2和SH2-ST4分別為GGVVIA和MVGGVV寡聚體的最小成核點。我們模擬結果顯示，在單層的GGVVIA和MVGGVV寡聚體中，疏水作用力扮演重要的角色以維持相鄰β-strand之間的穩定性。在相鄰的β-sheet間，疏水立體拉鍊在GGVVIA寡聚體中是由側鏈V3、V4和I5形成，而側鏈的疏水作用力對維持立體拉鍊扮演重要的角色。在MVGGVV寡聚體中，疏水立體拉鍊使相鄰的β-sheet能藉由疏水側鏈M1、V2、V5和V6緊密的結合在一起。在GGVVIA寡聚體中，將側鏈V3、V4和I5分別突變成Glycine，會直接導致相鄰β-strand之間的疏水作用力消失和破壞相鄰β-sheet間的疏水立體拉鍊。相同地， MVGGVV寡聚體的突變實結果顯示，突變組M1G、V2G、V5G和V6G會直接拉長相鄰β-strand間的距離且破壞疏水立體拉鍊。總結來說，我們的模擬結果提供詳細的原子尺度資訊來幫助了解GGVVIA和MVGGVV寡聚體的聚集特性。這結果可能可以作為設計新的抑制劑來防止Aβ胜肽進行纖維化。

關鍵字

神經退化性疾病 ； 阿茲海默症 ； 帕金森氏症 ； 亨丁頓舞蹈症 ； 類澱粉β胜肽立體拉鍊 ； 分子動態模擬 ； 類澱粉纖維

並列摘要

Several neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, are associated with amyloid fibrils formed by different polypeptides. Recently, the atomic structure of the amyloid-forming peptides GGVVIA and MVGGVV from the C-terminal hydrophobic segment of amyloid-β (Aβ) peptide has been determined and revealed a dry, tightly self-complementing structure between two β-sheets, termed as “steric zipper”. In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the structural stability and aggregation behavior of the GGVVIA and MVGGVV oligomers with various sizes. The results of both GGVVIA and MVGGVV oligomers showed that their structural stability increases with increasing the numbers of β-strands. Our results also showed that the two-sheet models exhibit higher structural stability than the one-sheet models, indicating that an extra β-sheet layer is necessary to stabilize the oligomers. We further suggested that the minimal nucleus seeds for GGVVIA and MVGGVV fibril formation could be SH2-ST2 and SH2-ST4 models, respectively. Our simulation results also revealed that the hydrophobic interactions between the adjacent β-strands within the same layer plays an important role in stabilizing both GGVVIA and MVGGVV oligomers. Between the two neighboring β-sheets, the hydrophobic steric zipper of GGVVIA formed via the side chains of V3, V4, and I5 plays a critical role in holding the hydrophobic steric zipper together. For the case of MVGGVV oligomers, the hydrophobic side chain of M1, V2, V5, and V6 also locks the hydrophobic steric zipper together between the two neighboring β-sheet layers. For GGVVIA oligomers, single glycine substitution at V3, V4, and I5 directly result in the loss of hydrophobic interactions between the adjacent β-strands and disrupt the hydrophobic steric zipper between these two β-sheets. Similarly, mutation simulations for MVGGVV showed that a single glycine residue substitution, M1G, V2G, V5G, and V6G, directly result in elongation between β-strands and disrupt the steric zipper between the two neighboring β-sheet layers. In summary, our simulation results provided detailed insights into understanding the aggregation behavior of the GGVVIA and MVGGVV oligomers in the atomic level. It may also be helpful for designing new inhibitors able to prevent the fibril formation of Aβ peptide.

並列關鍵字

Neurodegenerative diseases ； Alzheimer’s disease ； Parkinson’s disease ； Huntington’s diseases ； amyloid-β peptide ； steric zipper ； molecular dynamics (MD) simulation ； amyloid fibril

參考文獻

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