Molecular insights into the very early steps of Aβ1-42 pentameric protofibril disassembly by PGG: A molecular dynamics simulation study

[Display omitted] •Mechanisms of the very early steps of Aβ1-42 protofibril disassembly by PGG were studied.•The probability of β-sheet structure in Aβ1-42 protofibril was reduced by PGG.•PGG weakened the interactions between Chain-1 and Chain-2 in Aβ1-42 protofibril.•PGG markedly disrupted the Lys28-Ala42 salt bridges network in Aβ1-42 protofibril. Aβ peptide aggregates were the main targets to treat AD. Previous experimental study demonstrated that the 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucopyranose (PGG, containing 5 gallate moieties) dramatically destabilized the preformed Aβ fibril in vitro and in vivo. However, the mechanisms were still poorly understood. Herein, by performing molecular dynamics simulations, the detailed mechanisms of the very early steps of Aβ1-42 pentameric protofibril disassembly by PGG were explored. It was demonstrated that the binding of PGG molecules to Aβ1-42 pentameric protofibril disrupted the β-sheet structure, weakened the interactions between Chain-1 and Chain-2, and disturbed the Lys28-Ala42 salt bridges in Aβ1-42 pentameric protofibril. We found that the hydrophobic interactions, hydrogen bonds, pi-pi interactions and cation-pi interactions existed between PGG molecules and amino acid residues in the corner of L-shaped part (Phe4-Leu17) were conducive to the disaggregation of the close interactions between Chain-1 and Chain-2. Moreover, PGG molecules disrupted the Lys28-Ala42 salt bridges not only by the hydrogen bonds and cation-pi interactions with Lys28 but also through the interactions with C-terminal hydrophobic amino acid residues. We believed that our results could provide significant insights into the mechanisms of the very early steps of Aβ1-42 pentameric protofibril disassembly by PGG.