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12-Crown‑4 Ether Disrupts the Patient Brain-Derived Amyloid-β-Fibril Trimer: Insight from All-Atom Molecular Dynamics Simulations
journal contribution
posted on 2016-07-25, 00:00 authored by Nikhil Agrawal, Adam A. SkeltonRecent experimental
data elucidated that 12-crown-4 ether molecule
can disrupt Aβ40 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 Aβ40 fibril
disruption by 12-crown-4. In the present study we have used the Aβ40
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 β-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 Aβ 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 Aβ fibrils.