Five similar anthocyanidin molecules display distinct disruptive effects and mechanisms of action on _A1-42 protofibril: A molecular dynamic simulation study

Alzheimer's disease (AD) is associated with the deposition of amyloid-beta (A beta) fibrillary aggregates. Disaggregation of A beta fibrils is considered as one of the promising AD treatments. Recent experimental studies showed that anthocyanidins, one type of flavonoids abundant in fruits/vegetables, can disaggregate A beta fibrillary aggregates. However, their relative disruptive capacities and underlying mechanisms are largely unknown. Herein, we investigated the detailed interactions between five most common anthocyanidins (cyanidin, aurantinidin, peonidin, delphinidin, and pelargonidin) and A beta protofibril (an intermediate of A beta fibrillization) by performing microsecond molecular dynamic simulations. We found that all five anthocyanidins can destroy F4-L34-V36 hydrophobic core and K28-A42 salt bridge, leading to A beta protofibril destabilization. Aurantinidin exhibits the strongest damage to A beta protofibril (with the most severe disruption on K28-A42 salt bridges), followed by cyanidin (with the most destructive effect on F4-L34-V36 core). Detailed analyses reveal that the protofibrildestruction capacities of anthocyanidins are subtly modulated by the interplay of anthocyanidin-protofibril hydrogen bonding, hydrophobic, aromatic stacking interactions, which are dictated by the number or location of hydroxyl/methyl groups of anthocyanidins. These findings provide important mechanistic insights into A beta protofibril disaggregation by anthocyanidins, and suggest that aurantinidin/cyanidin may serve as promising starting-points for the development of new drug candidates against AD.