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

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.