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

Alzheimer's disease (AD) is associated with the aggregation of amyloid- (A) peptides into toxic fibrillar aggregates. Finding effective inhibitors of A 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 A fibrillization and reduce A cytotoxicity. However, the influence of Dih molecules on preformed A fibrils and the atomic-level details of interactions between Dih and A fibrils are largely unknown. In this work, we performed multiple molecular dynamics (MD) simulations for 1.2 s in total on the A(17-42) 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 (17)LVFFA(21) in the 1 region, the protofibril cavity and the C-terminal hydrophobic-groove spanning residues (31)IIGLM(35) in the 2 region. Binding to the C-terminal hydrophobic-groove slightly affects the structures of A(17-42) 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 -sheet in the 1 region. The dynamic process of Dih molecules entering the cavity of A(17-42) protofibrils is also investigated. We also examined the effect of Dih molecules on both U-shaped A(40)/A(42) protofibrils and S-shaped A(42) protofibrils by carrying out multiple MD simulations. Our simulations show that Dih molecules can destabilize both U-shaped and S-shaped A protofibrils by binding to the protofibril cavity. This study reveals the mechanism by which Dih molecules disrupt A protofibrils, which may offer new clues for the development of drug candidates for the treatment of AD.