The amyloid β-peptides (Aβs) are the main protein components of amyloid deposits in Alzheimer's disease (AD). Detailed knowledge of the structure and assembly dynamics of Aβis important for the development of properly targeted AD therapeutics. So far, the process of the monomeric Aβ 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 Aβ(17-42) oligomers associated with various numbers of monomers (dimer, trimer, tetramer, and pentamer). Our results showed that the structural stability of the Aβ(17-42) oligomers increases with increasing the number of monomer. We further demonstrated that the native hydrophobic contacts are positive correlated with the β-sheet contents, indicating that hydrophobic interaction plays an important role in maintaining the structural stability of the Aβ17-42) 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 hy-drophobic 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 hydro-phobic interactions and that the intermolecular contact pairs, Gly33-Gly33 and Gly37-Gly37, form a stable "molecular notch", which may mediate the packing of the β-sheet involving many other hydrophobic residues during the early stage of amyloid-like fibril formation.
|頁（從 - 到）||481-490|
|期刊||Journal of Biomolecular Structure and Dynamics|
|出版狀態||已發佈 - 二月 2009|
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