Molecular Dynamics Simulations of Ibuprofen Binding to A β Peptides

Abstract

Using replica exchange molecular dynamics simulations and the implicit solvent model we probed binding of ibuprofen to A β 10–40 monomers and amyloid fibrils. We found that the concave (CV) fibril edge has significantly higher binding affinity for ibuprofen than the convex edge. Furthermore, binding of ibuprofen to A β monomers, as compared to fibrils, results in a smaller free energy gain. The difference in binding free energies is likely to be related to the presence of the groove on the CV fibril edge, in which ibuprofen tends to accumulate. The confinement effect of the groove promotes the formation of large low-energy ibuprofen clusters, which rarely occur on the surface of A β monomers. These observations led us to suggest that the ibuprofen binding mechanism for A β fibrils is different from that for monomers. In general, ibuprofen shows a preference to bind to those regions of A β monomers (amino terminal) and fibrils (the CV edge) that are also the primary aggregation interfaces. Based on our findings and on available experimental data, we propose a rationale for the ibuprofen antiaggregation effect.