Abstract
Alzheimer’s disease (AD) is highly associated with self-aggregation of amyloid β (Aβ) proteins into fibrils. Inhibition of Aβ 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 Aβ aggregation, but the inhibition mechanisms are still unclear. In this work, these four polyphenols were selected to explore their interactions with the Aβ17–42 pentamer by molecular dynamics simulation. All four polyphenols can bind to the pentamer tightly but prefer different binding sites. Conversion of the β-sheet to the random coil, fewer interchain hydrogen bonds, and weaker salt bridges were observed after binding. Interestingly, different Aβ17–42 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 β-sheet offset and dissociation of the β1 sheet of chain E. This work reveals the interactions between the Aβ17–42 pentamer and four polyphenols and discusses the relationship between inhibitor structures and their inhibition mechanisms, which also provides useful guidance for screening effective Aβ aggregation inhibitors and drug design against AD.