Dihydrochalcone molecules destabilize Alzheimer's amyloid-β protofibrils through binding to the protofibril cavity.

Alzheimer's disease (AD) is associated with the aggregation of amyloid-β (Aβ) peptides into toxic fibrillar aggregates. Finding effective inhibitors of Aβ aggregation is a crucial step for the development of drugs against AD. Recent experiments reported that dihydrochalcone (Dih), a compound extracted from the daemonorops draco tree, could effectively inhibit Aβ fibrillization and reduce Aβ cytotoxicity. However, the influence of Dih molecules on preformed Aβ fibrils and the atomic-level details of interactions between Dih and Aβ fibrils are largely unknown. In this work, we performed multiple molecular dynamics (MD) simulations for 1.2 μs in total on the Aβ17-42 protofibrils with and without Dih molecules. We found that Dih molecules mostly bind to three different sites of the protofibril: the exterior central hydrophobic core (CHC) spanning residues 17LVFFA21 in the β1 region, the protofibril cavity and the C-terminal hydrophobic-groove spanning residues 31IIGLM35 in the β2 region. Binding to the C-terminal hydrophobic-groove slightly affects the structures of Aβ17-42 protofibrils, while binding to the exterior CHC and the cavity strongly destabilizes the protofibrils by mostly disrupting the D23-K28 salt bridges and the inter-peptide β-sheet in the β1 region. The dynamic process of Dih molecules entering the cavity of Aβ17-42 protofibrils is also investigated. We also examined the effect of Dih molecules on both U-shaped Aβ40/Aβ42 protofibrils and S-shaped Aβ42 protofibrils by carrying out multiple MD simulations. Our simulations show that Dih molecules can destabilize both U-shaped and S-shaped Aβ protofibrils by binding to the protofibril cavity. This study reveals the mechanism by which Dih molecules disrupt Aβ protofibrils, which may offer new clues for the development of drug candidates for the treatment of AD.