The most striking feature of Alzheimer’s disease (AD) is amyloid-β (Aβ) peptide fibrillation aggregation, thus inhibition of Aβ aggregation or destabilization the pre-existing fibril can be considered as a therapeutic strategy to treat AD. Peptide inhibitors, especially oligopeptides, have been frequently used as Aβ aggregation disruptors, known as β-sheet breaker peptides. However, as the simplest oligopeptide, dipeptides were fewer reported on the inhibition of protein aggregation. In addition, the chirality of amino acid residues also plays an important role in the inhibitory effect. Therefore, in this paper, a database (1600 species) containing all L- and D-type dipeptide molecules was first constructed, and then used to explore new β-sheet breaker peptides. Herein, we designed a strategy to filter the preferred β-sheet breaker dipeptides from dipeptide pools. Firstly, we constructed a library covering all kinds of dipeptides, considering comprehensive sequences and amino acid chirality of dipeptides. Then molecular docking and molecular dynamics simulations were performed to initially screen dipeptides that remained potential high affinity to Aβ protofibrils, and microsecond-level molecular dynamics simulations were carried out to find preferred β-sheet breaker dipeptides that maintained the optimal disruption performance on Aβ protofibrils. Meanwhile, replica exchange molecular dynamics simulations were performed to further filter the dipeptide that may also inhibit Aβ aggregation. The simulation demonstrated that DFLW, DWDF and DWDP were potential β-sheet breaker dipeptides and possessed considerable disruption performance on Aβ protofibrils, among which DWDP displayed optimal disruptive capacity on Aβ fibrils than the other two dipeptides by richer hydrogen bonds and hydrophobic interactions with Aβ protofibrils. Inhibition and disruption effects of DWDP on Aβ42 aggregation were also verified by thioflavin T fluorescence, transmission electron microscopes and cytotoxicity assay. This study presented a feasible strategy to explore novel dipeptides with superior Aβ fibril disruption ability as potential therapeutic agents for AD.

Computational screening strategy for exploring effective dipeptides disrupting Aβ42 protofibrils and inhibiting Aβ42 aggregation

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