Discovering Effective Chiral Dipeptides against Aβ(1–42) Aggregation by the Computational Screening Strategy

The β-sheet-breaker (BSB) peptides inhibiting amyloidogenic aggregation have been extensively studied. However, the inhibition efficacy of ultrashort chiral dipeptides remains inadequately understood. In this study, we proposed a computational screening strategy to identify chiral dipeptides as BSB with optimal antiaggregation performance against Aβ(1-42) aggregation. We constructed a complete dipeptide library encompassing all possible chiral sequence arrangements and then filtered the library by cascaded molecular docking-molecular dynamics (MD) simulation. Our screening strategy discovered dipeptide ^DW^DP (superscript for chirality) that displayed strong interactions with Aβ fibrils and inhibitory effects on Aβ aggregation, validated by subsequent experiments. Mechanistic investigation by both MD and replica-exchange molecular dynamics (REMD) simulations revealed that ^DW^DP interacts with Aβ by hydrophobic contacts and hydrogen bonds and thus inhibits Aβ intermolecular contacts and salt bridge formation, therefore inhibiting Aβ aggregation and disrupting Aβ aggregates. Totally, our strategy presents a viable approach to discover potential dipeptides with effective antiaggregation ability as potential therapeutic agents for Alzheimer's disease.