Explicit Solvent Molecular
Dynamics Simulations of
Aβ Peptide Interacting with Ibuprofen Ligands
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Abstract
Using all-atom explicit water model and replica exchange
molecular
dynamics, we study the interactions between Aβ monomer and nonsteroidal
anti-inflammatory drug ibuprofen, which is known to reduce the risk
of Alzheimer’s disease. Ibuprofen binding to Aβ is largely
governed by hydrophobic effect, and its binding site in Aβ peptide
is entirely composed of hydrophobic amino acids. Electrostatic interactions
between negatively charged ibuprofen ligands and positively charged
side chains make a relatively small contribution to binding. This
outcome is explained by the competition of ligand–peptide electrostatic
interactions with intrapeptide salt bridges. Consistent with the experiments,
the S-isomer of ibuprofen binds with stronger affinity to Aβ
than the R-isomer. Conformational ensemble of Aβ monomer in
ibuprofen solution reveals two structured regions, 19–25 (R1)
and 29–35 (R2), composed of turn/helix and helix structure,
respectively. The clustering technique and free energy analysis suggest
that Aβ conformational ensemble is mainly determined by the
formation of Asp23-Lys28 salt bridge and the hydrophobic interactions
between R1 and R2. Control simulations of Aβ peptide in ligand-free
water show that ibuprofen binding changes Aβ structure by promoting
the formation of helix and Asp23-Lys28 salt bridge. Implications of
our findings for Aβ amyloidogenesis are discussed