教師資料查詢 | 類別: 期刊論文 | 教師: 蔡旻燁 MIN-YEH TSAI (瀏覽個人網頁)

標題:Exploring the Aggregation Free Energy Landscape of the Amyloid-β Protein (1-40)
學年105
學期1
出版(發表)日期2016/10/18
作品名稱Exploring the Aggregation Free Energy Landscape of the Amyloid-β Protein (1-40)
作品名稱(其他語言)
著者Zheng, Weihua; Tsai, Min-Yeh; Chen, Mingchen; Wolynes, Peter G
單位
出版者
著錄名稱、卷期、頁數Proc. Natl. Acad. Sci. U.S.A., 113, 42, 11835
摘要A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1-40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer's disease.
關鍵字amyloid funnel;misfolding;nucleation
語言英文(美國)
ISSN0027-8424
期刊性質國外
收錄於SCI;
產學合作
通訊作者
審稿制度
國別美國
公開徵稿
出版型式,電子版,紙本
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