Molecular Dynamics Simulations of Anti-Aggregation Effect of Ibuprofen

AbstractUsing implicit solvent molecular dynamics and replica exchange simulations, we study the impact of ibuprofen on the growth of wild-type Aβ fibrils. We show that binding of ibuprofen to Aβ destabilizes the interactions between incoming peptides and the fibril. As a result, ibuprofen interference modifies the free energy landscape of fibril growth and reduces the free energy gain of Aβ peptide binding to the fibril by ≃2.5 RT at 360 K. Furthermore, ibuprofen interactions shift the thermodynamic equilibrium from fibril-like locked states to disordered docked states. Ibuprofen's anti-aggregation effect is explained by its competition with incoming Aβ peptides for the same binding site located on the fibril edge. Although ibuprofen impedes fibril growth, it does not significantly change the mechanism of fibril elongation or the structure of Aβ peptides bound to the fibril