The aggregation of amyloid-β (Aβ) peptides into senile plaques is a hallmark of Alzheimer's disease (AD) and is hypothesized to be the primary cause of AD related neurodegeneration. Previous studies have shown the ability of curcumin to both inhibit the aggregation of Aβ peptides into oligomers or fibrils and reduce amyloids in vivo. Despite the promise of curcumin and its derivatives to serve as diagnostic, preventative, and potentially therapeutic AD molecules, the mechanism by which curcumin and its derivatives bind to and inhibit Aβ fibrils' formation remains elusive. Here, we investigated curcumin and a set of curcumin derivatives in complex with a hexamer peptide model of the Aβ_1-42 fibril using nearly exhaustive docking, followed by multi-ns molecular dynamics simulations, to provide atomistic-detail insights into the molecules' binding and inhibitory properties. In the vast majority of the simulations, curcumin and its derivatives remain firmly bound in complex with the fibril through primarily three different principle binding modes, in which the molecules interact with residue domain ₁₇LVFFA₂₁, in line with previous experiments. In a small subset of these simulations, the molecules partly dissociate the outermost peptide of the Aβ_1-42 fibril by disrupting β-sheets within the residue domain ₁₂VHHQKLVFF₂₀. A comparison between binding modes leading or not leading to partial dissociation of the outermost peptide suggests that the latter is attributed to a few subtle key structural and energetic interaction-based differences. Interestingly, partial dissociation appears to be either an outcome of high affinity interactions or a cause leading to high affinity interactions between the molecules and the fibril, which could partly serve as a compensation for the energy loss in the fibril due to partial dissociation. In conjunction with this, we suggest a potential inhibition mechanism of Αβ_1-42 aggregation by the molecules, where the partially dissociated ₁₆KLVFF₂₀ domain of the outermost peptide could either remain unstructured or wrap around to form intramolecular interactions with the same peptide's ₂₉GAIIG₃₃ domain, while the molecules could additionally act as a patch against the external edge of the second outermost peptide's ₁₆KLVFF₂₀ domain. Thereby, individually or concurrently, these could prohibit fibril elongation.

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