Molecular insights into the structure destabilization effects of ECG and EC on the Aβ protofilament: An all-atom molecular dynamics simulation study

The formation of A beta into amyloid fibrils was closely connected to AD, therefore, the A beta aggregates were the primary therapeutic targets against AD. Previous studies demonstrated that epicatechin-3-gallate (ECG), which possessed a gallate moiety, exhibited a greater ability to disrupt the preformed A beta amyloid fibrils than epicatechin (EC), indicating that the gallate moiety was crucial. In the present study, the molecular mechanisms were investigated. Our results demonstrated that ECG had more potent disruptive impacts on the beta-sheet structure and K-28-A(42) salt bridges than EC. We found that ECG significantly interfered the interactions between Peptide-4 and Peptide-5. However, EC could not. The disruption of K-28-A(42) salt bridges by ECG was mainly due to the interactions between ECG and the hydrophobic residues located at C-terminus. Interestingly, EC disrupted the K-28-A(42) salt bridges by the interactions with C-terminal hydrophobic residues and the cation-pi interactions with K-28. Moreover, our results indicated that hydrophobic interactions, H-bonds, pi-pi interactions and cation-pi interactions between ECG and the bend of L-shaped region caused the disaggregation of interactions between Peptide-4 and Peptide-5. Significantly, gallate moiety in ECG had contributed tremendously to the disaggregation. We believed that our findings could be useful for designing prospective drug candidates targeting AD.