Computational Study of the Driving Forces and Dynamics of Curcumin Binding to Amyloid-β Protofibrils

Oligomeric aggregates of the amyloid-β (Aβ) peptide are believed to be the primary toxic species that initiate events leading to neurodegeneration and cognitive decline in Alzheimer’s disease (AD). Small molecules that interfere with Aβ aggregation and/or neurotoxicity are being investigated as potential therapeutics for AD, including naturally occurring polyphenols. We have recently shown that curcumin exerts a neuroprotective effect against Aβ40-induced toxicity on cultured neuronal cells through two possible concerted pathways, ameliorating Aβ oligomer-induced toxicity and inducing the formation of nontoxic Aβ oligomers, both of which involve curcumin binding to Aβ oligomers. To gain molecular-level insights into curcumin’s interaction with Aβ oligomers, we use all-atom molecular dynamics (MD) simulations to study the dynamics and energetics of curcumin binding to an Aβ protofibril composed of 24 peptides. Our results show that curcumin binds to specific hydrophobic sites on the protofibril surface and...