Molecular insight into the inhibition effect of trehalose on the nucleation and elongation of amyloid beta-peptide oligomers.

Soluble amyloid oligomers are a cytotoxic species in Alzheimer's disease, and the recent discovery that trehalose can prohibit aggregation of amyloid beta-peptide (Abeta) has received great attention. However, its inhibition mechanism remains unclear. In order to investigate the molecular mechanism of the inhibition effect, molecular dynamics simulations of Abeta(16-22) and Abeta(40) peptides at different trehalose concentrations (0-0.18 mol/L) are performed using an all-atom model. The simulations confirmed that Abeta(16-22) aggregation is prevented by trehalose in a dose-dependent manner, and it is found that the preferential exclusion effect of trehalose is the origin of its inhibition effects. Namely, there is preferential hydration on the peptide surface (3 A), and trehalose molecules cluster around the peptides at a distance of 4-5 A. At high trehalose concentrations, the preferential exclusion of trehalose leads to three sequential effects that prevent the nucleation and elongation of Abeta(16-22) oligomers. First, the secondary structures of Abeta(16-22) monomers are stabilized in the turn, bend, or coil, so the beta-sheet-rich structure that is prone to forming peptide oligomers is prevented. Second, the thin hydration layer and trehalose clusters can weaken hydrophobic interactions that lead to Abeta(16-22) aggregation. Third, more direct and indirect H-bonds form between trehalose and Abeta(16-22), which suppress the interpeptide hydrogen bonding. Analyses of the simulation data for a single Abeta(40) peptide indicate that trehalose can inhibit the nucleation and elongation of Abeta(40) by a similar mechanism with that on Abeta(16-22) oligomerization. The work has thus elucidated the molecular mechanism of trehalose on the inhibition of Abeta oligomeric aggregation.