Molecular dynamics simulations to investigate the aggregation behaviors of the a?(17–42) oligomers
Journal
Journal of Biomolecular Structure and Dynamics
Journal Volume
26
Journal Issue
4
Pages
481-490
Date Issued
2009
Author(s)
Abstract
The amyloid β-peptides (A?s) are the main protein components of amyloid deposits in Alzheimer's disease (AD). Detailed knowledge of the structure and assembly dynamics of A? is important for the development of properly targeted AD therapeutics. So far, the process of the monomeric A? 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?(17–42) oligomers associated with various numbers of monomers (dimer, trimer, tetramer, and pentamer). Our results showed that the structural stability of the A?(17–42) oligomers increases with increasing the number of monomer. We further demonstrated that the native hydrophobic contacts are positive correlated with the ?-sheet contents, indicating that hydrophobic interaction plays an important role in maintaining the structural stability of the A?(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 ?-sheet involving many other hydrophobic residues during the early stage of amyloid-like fibril formation. ? 2009 Taylor & Francis Group, LLC.
Subjects
Aggregation; Alzheimer's disease; Amyloid; A?; Hydrophobic; Molecular dynamics simulation; Molecular notch
SDGs
Other Subjects
Amino Acid Sequence; Amyloid beta-Peptides; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Molecular Sequence Data; Peptide Fragments; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Stability; Protein Structure, Secondary; amino acid; amyloid beta protein; amyloid beta protein[17-42]; glycine; monomer; Notch receptor; oligomer; unclassified drug; Alzheimer disease; article; beta sheet; carboxy terminal sequence; human; hydrophobicity; molecular dynamics; priority journal; protein aggregation; protein analysis; protein assembly; protein binding; protein domain; protein interaction; protein stability; protein structure; protein targeting; simulation
Type
journal article