Molecular Dynamics Simulations of Anti-Aggregation Effect of Ibuprofen

Using implicit solvent molecular dynamics and replica exchange simulations, we study the impact of ibuprofen on the growth of wild-type A beta fibrils. We show that binding of ibuprofen to A beta 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 A beta peptide binding to the fibril by similar or equal to 2.5 RTat 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 A beta 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 A beta peptides bound to the fibril.