Study on molecular mechanisms of destabilizing Aβ(1–42) protofibrils by licochalcone A and licochalcone B using molecular dynamics simulations

Amyloid-beta (Aβ) protofibrils are closely related to Alzheimer's disease. Their behaviors with or without the presence of Aβ fibrillization inhibitors have been intensively studied by molecular dynamics simulations. In this work, the molecular mechanisms of licochalcone A and licochalcone B on destabilizing Aβ(1–42) protofibrils are explored. It is found that both two licochalcones can disorder the configuration of the Aβ(1–42) protofibril. The stable interactions between the Aβ(1–42) protofibril and licochalcone A or licochalcone B are able to be formed. A reduction of the β-sheet structure contents and an increment of the random coil structures of Aβ(1–42) protofibril are observed in the presence of either licochalcone A or licochalcone B. The hydrogen bonds inside the Aβ(1–42) protofibril could be partially collapsed to varying degrees by two licochalcones. Furthermore, the van der Waals interactions between Aβ(1–42) protofibril and licochalcone A make an important contribution to the binding free energy, while the contribution of the electrostatic interactions between Aβ(1–42) protofibril and licochalcone B is more prominent in the binding affinity. Our work may help in the development of new drug candidates for disrupting the Aβ protofibril. [Display omitted] •The molecular mechanisms of licochalcone A and licochalcone B on destabilizing Aβ(1–42) protofibrils are explored.•The specific binding modes of two licochalcones with Aβ(1–42) protofibril are identified by molecular docking simulations.•The docked complexes are further evaluated based on molecular dynamics simulations.