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 that binding is generally associated with the concomitant complexation of curcumin into dimers, trimers, or tetramers. Curcumin also binds to the protofibril growth axis ends but without complexation. Analysis of the energetics of the binding process revealed that curcumin complexation contributes in an additive fashion to curcumin–Aβ protofibril interactions. Favorable curcumin–protofibril binding is driven by a combination of hydrophobic interactions between curcumin and protofibril, curcumin self-aggregation, and solvation effects. These interactions are likely critical in blocking Aβ oligomer toxicity and inducing the growth of the protofibrils into “off-pathway” wormlike fibrils observed experimentally.

Misfolding and aggregation of the amyloid-b (Ab) peptide into b-sheet enriched fibrils is a central pathogenic event that leads to severe cognitive impairment in neurodegenerative disorders such as Alzheimer's disease. Polyphenols and derivatives, many of which occur naturally, have been known for their therapeutic antioxidant and anti-inflammatory properties. More recently, their neuroprotective and anti-amyloidogenic properties are also becoming clear. We have shown that a particular polyphenol, curcumin found in turmeric, ameliorates toxicity of Ab40 oligomers and modulates the growth of Ab fibrils. Additionally, when Ab40 is coincubated with curcumin, curcumin induces the formation of off-pathway oligomers that are non-toxic. Herein, we investigate the molecular scale interaction between curcumin and oligomeric Ab using classical all-atom molecular dynamics (MD). Free energy calculations were carried out to obtain free energies of binding between curcumin complexes and the profibril (DG bind ) and free energies of curcumin complexation (DG cur-cur ). DG bind values were large and negative (up to À27 kcal/mol), indicating favorable binding of curcumin complexes to the fibril. DG cur-cur values were approximately À11 kcal/mol. Curcumin also binds to the ends of the fibrils with high binding energies and as single molecules. At these binding sites, curcumin is embedded into the fibril ends. The locations of these bound curcumin suggest that they could affect fibril growth which involves the addition of Ab monomers to ends of the fibrils. To investigate the effect of curcumin on fibril growth, we are using steered MD simulations to pull Ab monomers toward the protofibril ends in presence and absence of bound curcumin. This approach will illuminate curcumin impact pertaining to changes in b-sheet content of the monomer and behavior at the protofibril growth axis to support our experimental findings of altered fibril morphology in presence of curcumin.