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    Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/66762


    Title: A Replica-Exchange Molecular Dynamics Study of the Configurations of Alzheimer Amyloid beta-Peptide within Membrane: Implications for Aggregation and Toxicity
    Authors: 李健賓;Lee,Jian-Bin
    Contributors: 化學學系
    Keywords: 類澱粉蛋白質;胜肽;阿茲海默症;家族性阿茲海默症;組態;分子動態模擬;Amyloid beta peptide;peptides;Alzheimer’s disease;Familial Alzheimer’s disease;Configuration;Molecular Dynamic Simulation
    Date: 2015-01-28
    Issue Date: 2015-03-16 15:10:53 (UTC+8)
    Publisher: 國立中央大學
    Abstract: Amyloid-beta(Abeta)胜肽在腦中聚集形成類澱粉斑塊沉澱,堆積在神經細胞膜上造成神經細胞死亡,是阿茲海默症的主要特徵。Abeta胜肽的生成,是由類澱粉前驅蛋白被細胞膜上的beta和γ酵素切割後所生成的片段。因為Abeta的生成在含有生物膜的環境,所以我們對於Abeta胜肽在生物膜上的位置及結構有很大的興趣,也希望能更進一步得到Abeta在生物膜上的聚集機制與神經毒性的洞見。我們使用平行淬煉分子動態法搭配電場膜的模型,進行Abeta(25-35) 胺基酸突變及序列交換的研究和全長Abeta(1-40)以及家族性遺傳變異體E22Q-Abeta(1-40)、D23N-Abeta(1-40)、 E22Q/D23N-Abeta(1-40)的研究。我們根據Abeta(25-35)模擬的結果,有效的得知Abeta(25-35)及其衍生物,在膜環境中的組態與毒性之間的相關性,我們在完成此研究之後,補充了先前無法透過輸水性與毒性的關聯解釋的實驗結果。接下來進一步研究全長的Abeta(1-40)以及家族性遺傳變異體,相較於阿茲海默症,有些早發型阿茲海默症被稱為家族性阿茲海默症,具遺傳性的家族性阿茲海默症源自於基因的突變,早發型阿茲海默症的患者中,發現類澱粉蛋白的聚集量增加。從相關的文獻搜尋中,目前尚未有系統性的研究,關於家族性突變Abeta胜肽在生物膜的環境當中的分子動態模擬研究。根據我們模擬的結果顯示,家族性突變體與Abeta相比,N端的胺基酸與中心疏水核心之間的網絡連結有減少的趨勢。此外我們也觀察到了家族性突變體,中心疏水核心組態的轉變,較容易從低暴露在水中的組態,轉換成無結構並高暴露在水中的組態,從這樣的結果,我們推論較無結構且暴露在水中的中心疏水核心,可以加速家族性突變的Aβ的聚集過程。本研究合理解釋了家族性阿茲海默症的Aβ為何能快速的聚集,且從藥物設計的角度上,提供藥物設計的方向,設計合理的藥物及療法。;Extracellular deposits of amyloidbeta (Abeta) aggregates in brain is the hallmark of Alzheimer’s disease (AD). Abeta peptide is produced from the amyloid precursor protein (APP) within membrane by the proteolytic action of thebeta- and γ-secretases. Therefore, it is crucial to determine the configuration of Abeta peptide within a membrane to provide insights at atomic levels for the aggregation mechanism and toxicity. In this thesis, we employed replica-exchange molecular dynamics in conjunction with an implicit membrane model to investigate the mutation and sequence effects of short Abeta(25-35) fragment and familial mutations (E22Q (Dutch), D23N (Iowa) and E22Q/D23N (Dutch/Iowa) mutants) of full length Abeta(1–40) peptide on their configurations within a membrane. Our work on Abeta(25-35) and its mutants correlated the configurations of peptides within membrane with their toxicities complementing the hydrophobicity-toxicity relationship. In the work of familial mutations of Abeta, we find that the central hydrophobic core (CHC) (residues 17-21) of familial mutants is less protected and thus more exposed to the solvent than that of Abeta(1–40) peptide due to their weal long-range contacts with the N-terminal (residues 1-16). Moreover, for the familial mutants, their energy barriers for the inter-conversion of the CHC configurations between membrane and water phases is lower than that of Abeta(1–40). Therefore, it is faster for the familial mutants to convert their CHCs from membrane (less surface-exposed) to water phase (highly surface-exposed), when their CHC populations in the water phase are decreased (e.g. aggregated). As the amyloid fibril is deposited on membrane, these findings are helpful to understand the experimental observations that the familial Abeta peptides aggregate much faster than that of Abeta(1–40). This study provides the insight for the rational drug design to prevent amyloid associated diseases.
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