Molecular dynamics simulations reveal the mechanism of graphene oxide nanosheet inhibition of Aβ₁–₄₂ peptide aggregation

The aggregation of the amyloid-beta (Aβ) peptides into toxic β-sheet-rich oligomers, protofibrils and mature fibrils is the major pathological hallmark of Alzheimer's disease (AD). Inhibiting the β-sheet formation and fibrillization of Aβ peptides is considered an important treatment strategy for AD. Graphene oxide (GO) has attracted particular interest in the anti-aggregation of amyloid proteins due to its good ability of crossing the blood-brain barrier (BBB), low cytotoxicity and good biocompatibility. Recent experiments reported that GO nanosheets could strongly inhibit the fibril formation of Aβ₁₋₄₂ and reduce its cytotoxicity. However, the mechanism of suppressing Aβ₁₋₄₂ fibrillization by GO nanosheets is not well understood. Aβ₁₋₄₂ dimer is the smallest toxic oligomer of Aβ₁₋₄₂ aggregation. As a starting step to understand the inhibitory effect of GO nanosheets towards Aβ₁₋₄₂ aggregation, we investigated the conformational distribution of the Aβ₁₋₄₂ dimer with or without GO nanosheets by performing explicit-solvent replica exchange molecular dynamics simulations. Our simulations showed that Aβ₁₋₄₂ peptides could form diverse β-sheet rich dimeric conformations, whereas those conformations were significantly inhibited after the addition of GO nanosheets. We found that GO suppressed the β-sheet formation of Aβ₁₋₄₂ mostly by weakening inter-peptide interactions mostly via salt bridge, hydrogen bonding and cation-π interactions with charged residues D1, E3, R5, D7, E11, K16, E22, K28 and A42. The π-π and hydrophobic interactions between GO and Aβ₁₋₄₂ also play a role in the inhibition of Aβ aggregation. This study provides mechanistic insights into Aβ₁₋₄₂ aggregation and amyloid inhibition by GO nanosheets, which may provide new clues for the development of therapeutic candidates against AD.