Understanding the Molecular Mechanisms of Polyphenol Inhibition of Amyloid β Aggregation

Alzheimer's disease (AD) is highly associated with self-aggregation of amyloid beta (A beta) proteins into fibrils. Inhibition of A beta aggregation by polyphenols is one of the major therapeutic strategies for AD. Among them, four polyphenols (brazilin, resveratrol, hematoxylin, and rosmarinic acid) have been reported to be effective at inhibiting A beta aggregation, but the inhibition mechanisms are still unclear. In this work, these four polyphenols were selected to explore their interactions with the A beta 17-42 pentamer by molecular dynamics simulation. All four polyphenols can bind to the pentamer tightly but prefer different binding sites. Conversion of the beta-sheet to the random coil, fewer interchain hydrogen bonds, and weaker salt bridges were observed after binding. Interestingly, different A beta 17-42 pentamer destabilizing mechanisms for resveratrol and hematoxylin were found. Resveratrol inserts into the hydrophobic core of the pentamer by forming hydrogen bonds with Asp23 and Lys28, while hematoxylin prefers to bind beside chain A of the pentamer, which leads to beta-sheet offset and dissociation of the beta 1 sheet of chain E. This work reveals the interactions between the A beta 17-42 pentamer and four polyphenols and discusses the relationship between inhibitor structures and their inhibition mechanisms, which also provides useful guidance for screening effective A beta aggregation inhibitors and drug design against AD.