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)
著者 Zheng, Weihua; Tsai, Min-Yeh; Chen, Mingchen; Wolynes, Peter G
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 en_US
ISSN 0027-8424
期刊性質 國外
收錄於 SCI
國別 USA
出版型式 ,電子版,紙本

機構典藏連結 ( http://tkuir.lib.tku.edu.tw:8080/dspace/handle/987654321/117164 )