https://scholars.lib.ntu.edu.tw/handle/123456789/428489
標題: | Modeling the Alzheimer A beta(17-42) fibril architecture: Tight intermolecular sheet-sheet association and intramolecular hydrated cavities | 作者: | Zheng, Jie Jang, Hyunbum Ma, Buyong CHUNG-JUN TSAI Nussinov, Ruth |
公開日期: | 2007 | 卷: | 93 | 期: | 9 | 起(迄)頁: | 3046-3057 | 來源出版物: | Biophysical Journal | 摘要: | We investigate Aβ17-42 protofibril structures in solution using molecular dynamics simulations. Recently, NMR and computations modeled the Aβ protofibril as a longitudinal stack of U-shaped molecules, creating an in-parallel β-sheet and loop spine. Here we study the molecular architecture of the fibril formed by spine-spine association. We model in-register intermolecular β-sheet-β-sheet associations and study the consequences of Alzheimer's mutations (E22G, E22Q, E22K, and M35A) on the organization. We assess the structural stability and association force of Aβ oligomers with different sheet-sheet interfaces. Double-layered oligomers associating through the C-terminal-C-terminal interface are energetically more favorable than those with the N-terminal-N-terminal interface, although both interfaces exhibit high structural stability. The C-terminal-C-terminal interface is essentially stabilized by hydrophobic and van der Waals (shape complementarity via M35-M35 contacts) intermolecular interactions, whereas the N-terminal-N-terminal interface is stabilized by hydrophobic and electrostatic interactions. Hence, shape complementarity, or the "steric zipper" motif plays an important role in amyloid formation. On the other hand, the intramolecular Aβ β-strand-loop-β-strand U-shaped motif creates a hydrophobic cavity with a diameter of 6-7Å, allowing water molecules and ions to conduct through. The hydrated hydrophobic cavitiesmayallow optimization of the sheet association and constitute a typical feature of fibrils, in addition to the tight sheet-sheet association. Thus, we propose that Aβ fiber architecture consists of alternating layers of tight packing and hydrated cavities running along the fibrillar axis, which might be possibly detected by high-resolution imaging. © 2007 by the Biophysical Society. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/428489 https://www.scopus.com/inward/record.uri?eid=2-s2.0-36148983867&doi=10.1529%2fbiophysj.107.110700&partnerID=40&md5=09f5341505ea2ef6dcebe98cf387b602 |
ISSN: | 0006-3495 | DOI: | 10.1529/biophysj.107.110700 | SDG/關鍵字: | amyloid; amyloid beta protein; amyloid beta protein (17 42); amyloid beta-protein (17-42); peptide fragment; unclassified drug; water; Alzheimer disease; amino terminal sequence; article; beta sheet; carboxy terminal sequence; molecular dynamics; nuclear magnetic resonance spectroscopy; protein motif; chemical structure; chemistry; computer simulation; human; metabolism; protein conformation; protein secondary structure; protein tertiary structure; thermodynamics; Alzheimer Disease; Amyloid beta-Protein; Computer Simulation; Humans; Models, Molecular; Peptide Fragments; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Thermodynamics; Water |
顯示於: | 數學系 |
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