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 beta-amyloid peptide (A beta(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 A beta(1-42) aggregation by different molecules is attributed to preventing of A beta(1-42) conformational transition from alpha-helix to the beta-sheet structure. However, our structural analysis shows that the pure water and aqueous solution of the CB[7] denature the native A beta(1-42) alpha-helix structure forming different compactness and unfolded conformations, not in beta-sheet form. On the other hand, in the three CB[7]@A beta(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]@A beta(1-42) complex was observed stable Asp23-Lys28 salt bridge with an average distance of 0.36 nm. All CB[7]@A beta(1-42) complexes are very stable with binding free energy lowest than similar to-50 kcal/mol between the CB[7] and A beta(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]@A beta(1-42) complex with the fibril lattice, and not due to the transition from alpha-helix to beta-sheet following the dock-lock mechanism. Communicated by Ramaswamy H. Sarma

Automated summary

The study revealed that CB[7] prevents the elongation of Aβ(1-42) protofibrils by disrupting the Asp23-Lys28 salt bridge and through steric effects, rather than through the transition from alpha-helix to beta-sheet as previously proposed.