Amyloid-β (Aβ) 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 Aβ into higher-order structures is to develop molecules that
inhibit the early stages of aggregation, i.e., dimerization. Under
physiological conditions, the Aβ 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 Aβ dimer was generated by an efficient
sampling method with constraints based on ion mobility mass spectrometry
data. Here, we make use of the Aβ 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 Aβ dimer.
The simulations show that the aromatic residues of Aβ, 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.
Amyloid-β (Aβ) 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 Aβ into higher order structures is to develop molecules that inhibit the early stages of aggregation, i.e. dimerization. Under physiological conditions the Aβ 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 work, a highly heterogeneous library of conformers of the Aβ dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aβ 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 Aβ dimer. The simulations show that the aromatic residues of Aβ 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.
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