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 beta-peptide (A beta) 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 A beta. 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 A beta monomers and dimers. Through 90 simulations totaling 23.65 mu s, we found that treatment of A beta peptides with morin largely does not affect secondary structure content, unless a large molar excess of morin is present. However, in simulations of A beta monomers and dimers, morin affected the tertiary and quaternary structure of A beta, even at low concentrations that have been used experimentally. Thus it appears that despite the inability of morin to fully block A beta aggregation or beta-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.