In-Silico study of Destabilizing Alzheimer’s Aβ42 Protofibrils with Curcumin.

Abstract

Aggregation of amyloid beta (Aβ) peptides leads to formation of fibrilar, soluble oligomers, and their deposition is a key event in progression of Alzheimer’s disease (AD). Recent experimental studies of (Curcumin) showed\ significant Aβ aggregation inhibition, but its molecular mechanism is not yet clear. Hence, the present study aims at exploring the underlying mechanism of destabilization and inhibition of aggregation of the Aβ protofibril by Curcumin at the molecular level. Molecular docking analysis shows that Curcumin binds to chain E of the Aβ protofibril through hydrogen bonding interactions. Comparative molecular dynamics simulations depict the binding of Curcumin at the edge of chain E, and its partially inserted conformation at the hydrophobic core destabilizes the Aβ protofibril. Its binding causes loss of hydrophobic contacts, leading to a partial opening of tightly packed β-sheet protofibrils. The hydration effect of salt bridge between the amino group of Lys28 and the oxygen atom of Curcumin contributes in destabilization of Aβ protofibrils. Binding free energy calculations of Curcumin and the Aβ protofibril showed that van der Waals interactions are dominant over the others. Thus, our results revealed that Curcumin interacts mainly with the hydrophobic core along with positively charged residues of the Aβ protofibril for effective destabilization. Thus, this structural information could be useful to design new inhibitors to control the aggregation of Aβ protofibrils in AD patients.