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

Amyloid-beta (A ss) protofibrils are closely related to Alzheimer's disease. Their behaviors with or without the presence of A ss fibrillization inhibitors have been intensively studied by molecular dynamics simulations. In this work, the molecular mechanisms of licochalcone A and licochalcone B on destabilizing A ss(1-42) protofibrils are explored. It is found that both two licochalcones can disorder the configuration of the A ss(1-42) protofibril. The stable interactions between the A ss(1-42) protofibril and licochalcone A or licochalcone B are able to be formed. A reduction of the ss-sheet structure contents and an increment of the random coil structures of A ss(1-42) protofibril are observed in the presence of either licochalcone A or licochalcone B. The hydrogen bonds inside the A ss (1-42) protofibril could be partially collapsed to varying degrees by two licochalcones. Furthermore, the van der Waals interactions between A ss(1-42) protofibril and licochalcone A make an important contribution to the binding free energy, while the contribution of the electrostatic interactions between A ss(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 A ss protofibril.