期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 26, 期 4, 页码 481-490出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2009.10507263
关键词
A beta; Amyloid; Alzheimer's disease; Aggregation; Molecular dynamics simulation; Hydrophobic; Molecular notch
资金
- National Science Council of Taiwan [NSC 95-2221-E-027-089]
The amyloid beta-peptides (A beta s) are the main protein components of amyloid deposits in Alzheimer's disease (AD). Detailed knowledge of the structure and assembly dynamics of A beta is important for the development of properly targeted AD therapeutics. So far, the process of the monomeric A beta assembling into oligomeric fibrils and the mechanism underlying the aggregation process remain unclear. In this study, several molecular dynamics simulations were conducted to investigate the aggregation behaviors of the A beta(17-42) oligomers associated with various numbers of monomers (dimer, trimer, tetramer, and pentamer). Our results showed that the structural stability of the A beta(17-42) oligomers increases with increasing the number of monomer. We further demonstrated that the native hydrophobic contacts are positive correlated with the beta-sheet contents, indicating that hydrophobic interaction plays an important role in maintaining the structural stability of the AP(17-42) oligomers, particularly for those associated with more monomers. Our results also showed that the stability of the C-terminal hydrophobic segment 2 (residues 30-42) is higher than that of the N-terminal hydrophobic segment 1 (residues 17-21), suggesting that hydrophobic segment 2 may act as the nucleation site for aggregation. We further identified that Met35 residue initiates the hydrophobic interactions and that the intermolecular contact pairs, Gly33-Gly33 and Gly37-Gly37, form a stable molecular notch, which may mediate the packing of the beta-sheet involving many other hydrophobic residues during the early stage of amyloid-like fibril formation.
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