12-Crown-4 Ether Disrupts the Patient Brain-Derived Amyloid-β-Fibril Trimer: Insight from All-Atom Molecular Dynamics Simulations

Recent experimental data elucidated that 12 crown-4 ether molecule can disrupt A beta 40 fibrils but the mechanism of disruption remains elusive. We have performed a series of all-atom molecular dynamics simulations to study the molecular mechanism of A beta 40 fibril disruption by 12-crown-4. In the present study we have used the A beta 40 fibril trimer as it is the smallest unit that maintains a stable U-shaped structure, and serves as the nucleus to form larger fibrils. Our study reveals that 12-crown-4 ether can enter into the hydrophobic core region and form competitive, hydrophobic interactions with key hydrophobic residues; these interactions break the intersheet hydrophobic interactions and lead to the opening of the U-shaped topology and a loss of beta-sheet structure. Furthermore, we observed periods of time when 12-crown-4 was in the hydrophobic core and periods of time when it interacted with Lys28 (chain C), a "tug of war"; the 12-crown-4 binding with Lys28 destabilizes the salt-bridge between Asp23 and Lys28. In addition to the two aforementioned binding modes, the 12-crown-4 binds with Lys16, which is known to form a salt-bridge with Glu22 in antiparallel arranged A beta fibrils. Our results are in good agreement with experimental results and suggest that molecules that have the ability to interact with both the hydrophobic core region and positively charged residues could serve as potential inhibitors of A beta fibrils.