Molecular Insight into the Inhibition Effect of Trehalose on the Nucleation and Elongation of Amyloid β-Peptide Oligomers

Abstract

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.

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

“…It is at the concave edge that new peptides would attach in the unidirectional growth model of the Aβ fibril. Ibuprofen formed clusters within the groove of the concave edge, precluding the attachment of additional Aβ peptides, a hypothesis confirmed by Chang et al 114 The authors further observed that interactions between ibuprofen and the peptide side chains 102 and model parallel β-strands (right) similar to those considered by Convertino et al 99 The parallel β-sheet structure is also used to illustrate the approximate binding sites of the indicated molecules to antiparallel β-sheet models considered by Viet et al 65 and Liu et al 101 were principally responsible for the ibuprofen−Aβ interaction, with few contacts formed involving Aβ backbone groups. Takeda et al performed very similar simulations with naproxen, 112 finding that, like ibuprofen, naproxen bound to the concave edge of the Aβ 10−40 fibril in order to preclude the attachment of other Aβ peptides.…”

“…Though the solvent is often viewed as a passive entity in most simulations, several studies have shown that water-mediated interactions may play a significant role in Aβ aggregate stability 120 and the interactions of Aβ with small molecules. 101,110 Several other studies summarized here employed implicit solvent representation, 99,100,111−114 though it is unclear what, if any, effects can be attributed to the absence of explicit water molecules. The other technique used to reduce the degrees of freedom in the system is the application of coarse-grained force fields, which have been utilized in several studies of Aβ dynamics.…”

“…In addition, Liu et al found an important role in hydration/dehydration in the binding of trehalose and EGCG to Aβ. 101,110 These results suggest that solvent representation is an important consideration in these simulations and that perhaps water-mediated interactions need to be explicitly considered to gain rigorous insight into interactions of some small molecules with Aβ.…”

“…101 The authors found that trehalose destabilized the β-sheet structure adopted by Aβ 16−22 , concomitant with a change in the hydration of the aggregates which gave rise to both direct and water-mediated hydrogen bonding of trehalose to Aβ 16−22 . These hydrogen bonding interactions destabilized existing aggregates and inhibited association of any additional Aβ 16−22 peptides with the aggregate, though a large molar excess of trehalose was required to produce this phenomenon.…”

‘Click’ assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

“…These explanations are consistent with molecular dynamics simulations which showed that preferential exclusion of trehalose is the origin of its inhibition of Aβ40 aggregation, partly due to stabilization of monomers with -helical structure so that β-sheet structure is prevented. 59 Compounds that retard Aβ aggregation by stabilizing helical structure may be of therapeutic benefit in AD because nascent Aβ generated by -secretase cleavage of transmembrane protein C99 (APP 672-770 , also called -CTF) is likely to comprise substantial helical content, since residues 17-23 of Aβ arise from the C99 "N-helix" (APP 688-694 ) and residues 29-40/42 of Aβ (APP 700-711/713 ) originate from within the C99 helical transmembrane domain (APP 700-723 ). 60 The effect of trehalose glycocluster 10 on Aβ40-induced neurotoxicity was studied using a cell-based trypan blue dye exclusion assay.…”