Morin inhibits the early stages of amyloid β-peptide aggregation by altering tertiary and quaternary interactions to produce "off-pathway" structures.

Alzheimer's disease is a debilitating neurodegenerative disorder whose pathology has been linked to the aggregation and deposition of the amyloid β-peptide (Aβ) in neural tissue. A truly effective therapeutic agent remains elusive, and attention has recently turned to the use of natural products as effective antiaggregation compounds, directly targeting Aβ. Although a wealth of in vitro and in vivo evidence suggests these compounds or their derivatives might be beneficial, a detailed understanding of the mechanism by which they act remains largely unknown. Using atomistic, explicit-solvent molecular dynamics simulations, we have investigated the association of the flavonoid morin with Aβ monomers and dimers. Through 90 simulations totaling 23.65 μs, we found that treatment of Aβ peptides with morin largely does not affect secondary structure content, unless a large molar excess of morin is present. However, in simulations of Aβ monomers and dimers, morin affected the tertiary and quaternary structure of Aβ, even at low concentrations that have been used experimentally. Thus it appears that despite the inability of morin to fully block Aβ aggregation or β-strand formation, we observe structures with altered tertiary and quaternary interactions, which may represent "off-pathway" aggregates that have been proposed previously. The simulations presented here add important new details to the mechanism of these processes.