Abstract
In this study, all-atom 50 ns molecular dynamics simulations are performed on the full-length amyloid beta (Aβ) monomers (WT-Aβ(1−40) and WT-Aβ(1−42)) and their oxidized forms (Met35(O)-Aβ(1−40) and Met35(O)-Aβ(1−42)) in aqueous solution. The effects of the oxidation state of Met35 and the presence of dipeptide (Ile41-Ala42) on the secondary structures of the three distinct regions (the central hydrophobic core region 17−21 (LVFFA), the loop 23−28 (DVGSNK), and the second hydrophobic domain 29−35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with the available experimental information. Our simulations indicate that the WT-Aβ(1−40) monomer adopts an overall β-hairpin-like structure, which is promoted by the turn region (24−27). This turn region is stabilized through salt-bridge formation between the Asp23 and Lys28 residues. In contrast, the overall structure of the oxidized (Met35(O)-Aβ(1−40)) monomer can be divided into three well-defined bend regions separated by coil segments. These structural differences may be critical for the measured decrease in the rate of aggregation of Met35(O)-Aβ(1−40) peptide. In the WT-Aβ(1−42) monomer, in comparison to the WT-Aβ(1−40), the Asp23−Lys28 salt bridge is absent, and consequently, the turn in the middle (24−27) region has a smaller curvature. The observed difference in the aggregation rates of these two peptides may be related to the opening of the turn (24−27) stabilized by the Asp23−Lys28 salt bridge. For WT-Aβ(1−42), in the absence of this salt bridge, the unfolding and aggregation events may be more favorable than for WT-Aβ(1−40).
