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In this study, comparable molecular dynamic (MD) simulations of 1.2 microseconds were performed to clarify the prevention of the β-amyloid peptide (Aβ 1–42 ) aggregation by cucurbit[7]uril (CB[7]). The accumulation of this peptide in the brain is one of the most harmful in Alzheimer’s disease. The inhibition mechanism of Aβ 1–42  aggregation by different molecules is attributed to preventing of Aβ 1–42  conformational transition from α-helix to the β-sheet structure. However, our structural analysis shows that the pure water and aqueous solution of the CB[7] denature the native Aβ 1–42  α-helix structure forming different compactness and unfolded conformations, not in β-sheet form. On the other hand, in the three CB[7]@Aβ 1–42  complexes, it was observed the encapsulation of N-terminal (Asp1), Lys16, and Val36 by CB[7] along the MD trajectory, and not with aromatic residues as suggested by the literature. Only in one CB[7]@Aβ 1–42  complex was observed stable Asp23-Lys28 salt bridge with an average distance of 0.36 nm. All CB[7]@Aβ 1–42  complexes are very stable with binding free energy lowest than ∼–50 kcal/mol between the CB[7] and Aβ 1-42  monomer from MM/PBSA calculation. Therefore, herein we show that the mechanism of the prevention of elongation protofibril by CB[7] is due to the disruption of the Asp23-Lys28 salt bridge and steric effects of CB[7]@Aβ 1–42  complex with the fibril lattice, and not due to the transition from α-helix to β-sheet following the dock-lock mechanism. Communicated by Ramaswamy H. Sarma

Insights into β-amyloid transition prevention by cucurbit[7]uril from molecular modeling