Interactions of Curcumin's Degradation Products with the Aß42 Dimer: A Computational Study.

Amyloid-ß (Aß) dimers are the smallest toxic species along the amyloid-aggregation pathway and among the most populated oligomeric accumulations present in the brain affected by Alzheimer's disease (AD). A proposed therapeutic strategy to avoid the aggregation of Aß into higher-order structures is to develop molecules that inhibit the early stages of aggregation, i.e., dimerization. Under physiological conditions, the Aß dimer is highly dynamic and does not attain a single well-defined structure but is rather characterized by an ensemble of conformations. In a recent study, a highly heterogeneous library of conformers of the Aß dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aß dimer library to study the interaction with two curcumin degradation products, ferulic aldehyde and vanillin, by molecular dynamics (MD) simulations. Ensemble docking and MD simulations are used to provide atomistic detail of the interactions between the curcumin degradation products and the Aß dimer. The simulations show that the aromatic residues of Aß, and in particular 19FF20, interact with ferulic aldehyde and vanillin through π-π stacking. The binding of these small molecules induces significant changes on the 16KLVFF20 region.