▎ 摘　　要

The aggregation of the amyloid-beta (Ab) peptides into toxic b-sheet-rich oligomers, protofibrils and mature fibrils is the major pathological hallmark of Alzheimer's disease (AD). Inhibiting the b-sheet formation and fibrillization of Ab 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 A beta(1-42) and reduce its cytotoxicity. However, the mechanism of suppressing A beta(1-42) fibrillization by GO nanosheets is not well understood. A beta(1-42) dimer is the smallest toxic oligomer of A beta(1-42) aggregation. As a starting step to understand the inhibitory effect of GO nanosheets towards A beta(1-42) aggregation, we investigated the conformational distribution of the A beta(1-42) dimer with or without GO nanosheets by performing explicit-solvent replica exchange molecular dynamics simulations. Our simulations showed that A beta(1-42) peptides could form diverse b-sheet rich dimeric conformations, whereas those conformations were significantly inhibited after the addition of GO nanosheets. We found that GO suppressed the b-sheet formation of A beta(1-42) mostly by weakening inter-peptide interactions mostly via salt bridge, hydrogen bonding and cation-p interactions with charged residues D1, E3, R5, D7, E11, K16, E22, K28 and A42. The p-p and hydrophobic interactions between GO and A beta(1-42) also play a role in the inhibition of Ab aggregation. This study provides mechanistic insights into A beta(1-42) aggregation and amyloid inhibition by GO nanosheets, which may provide new clues for the development of therapeutic candidates against AD.