Insights into Molecular Mechanisms of EGCG and Apigenin on Disrupting Amyloid-Beta Protofibrils Based on Molecular Dynamics Simulations

The fibrillization and deposition of amyloid-beta (Afi) protofibrils are one of the important factors leading to Alzheimer's disease. Molecular dynamics simulations can offer information on intermolecular interaction mechanisms between Afi protofibrils and Afi fibrillization inhibitors. Here, in this work, we explore the early molecular mechanisms of (-)-epigallocatechin-3-gallate (EGCG) and apigenin on disrupting Afi42 protofibrils based on molecular simulations. The binding modes of EGCG and apigenin with the Afi42 protofibril are obtained. Furthermore, we compare the behavioral mechanisms of EGCG and apigenin on disturbing the Afi42 protofibril. Both EGCG and apigenin are able to decrease the proportion of the fi-sheet and bend structures of the Afi42 protofibril while inducing random coil structures. The results of hydrogen bonds and D23-K28 salt bridges illustrate that EGCG and apigenin have the ability of destabilizing the Afi42 protofibril. Meanwhile, the van der Waals interactions between the EGCG and Afi42 protofibril are shown to be larger than that of apigenin with the Afi42 protofibril, but the electrostatic interactions between apigenin and the Afi42 protofibril are dominant in the binding affinity. Our findings may help in designing effective drug candidates for disordering the Afi protofibril and impeding Afi fibrillization.