Molecular Insight into the Inhibition Effect of Trehalose on the Nucleation and Elongation of Amyloid β-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 (A beta) 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 A beta(16-22) and A beta(40) peptides at different trehalose concentrations (0-0.18 mol/L) are performed using an all-atom model. The simulations confirmed that A beta(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 angstrom), and trehalose molecules cluster around the peptides at a distance of 4-5 angstrom. At high trehalose concentrations, the preferential exclusion of trehalose leads to three sequential effects that prevent the nucleation and elongation of A beta(16-22) oligomers. First, the secondary structures of A beta(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 A beta(16-22) aggregation. Third, more direct and indirect H-bonds form between trehalose and A beta(16-22), which suppress the interpeptide hydrogen bonding. Analyses of the simulation data for a single A beta(40) peptide indicate that trehalose can inhibit the nucleation and elongation of A beta(40) by a similar mechanism with that on A beta(16-22) oligomerization. The work has thus elucidated the molecular mechanism of trehalose on the inhibition of A beta oligomeric aggregation.