Dissecting the Inhibitory Mechanism of the αB-Crystallin Domain against Aβ₄₂ Aggregation and Its Effect on Aβ₄₂...

Alzheimer's disease (AD) is related to the misfolding and aggregation of amyloid-β (Aβ) protein, and its major pathological hallmark is fibrillary β-amyloid plaques. Impeding the formation of Aβ β-structure-rich aggregates and dissociating Aβ fibrils are considered potent strategies to suppress the onset and progression of AD. As a molecular chaperone, human αB-crystallin has received extensive attention in the inhibition of protein aggregation. Previous experiments reported that the structured core region of αB-crystallin (αBC) exhibits a better preventive effect on Aβ aggregation and toxicity than the full-length protein. However, the molecular mechanism behind the effect of inhibition remains mostly unknown. Herein, we carried out six 500 ns molecular dynamics (MD) simulations to investigate the inhibitory mechanism of αBC on Aβ₄₂ aggregation. Our simulations show that αBC greatly impedes the formation of β-structure contents. We find that the binding of αBC to the Aβ₄₂ monomer is driven by polar, hydrophobic, and H-bonding interactions. To explore whether αBC could destabilize Aβ₄₂ protofibrils, we also carried out MD simulations of Aβ₄₂ protofibrils with and without αBC. The results show that αBC interacts with three binding sites of the Aβ₄₂ protofibril, and the binding is mainly driven by polar and H-bonding interactions. The binding of αBC at these three sites has a preferred dissociation effect on the β-structure content, kink angle, and K28-A42 salt bridges. Overall, this study not only discloses the molecular mechanism of αBC against Aβ₄₂ aggregation but also demonstrates the disruption effects of αBC on Aβ₄₂ protofibrils, which yields an avenue for designing anti-AD drug candidates.