Edaravone inhibits the conformational transition of amyloid-β42: insights from molecular dynamics simulations.

Previous work has shown that edaravone inhibits fibrillogenesis of amyloid-β protein (Aβ). However, the detailed mechanism by which edaravone inhibits the conformational transition of the Aβ42 monomer is not known at the molecular level. Here, explicit-solvent molecular dynamics (MD) simulations were coupled with molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method to address the issue. MD simulations confirmed that edaravone inhibits the conformational transition of the Aβ42 monomer in a dose-dependent manner. It was found that the direct interactions between edaravone and Aβ42 are responsible for its inhibiting effects. The analysis of binding free energy using the MM-PBSA method demonstrated that the nonpolar interactions provide favourable contributions (about -71.7 kcal/mol). Conversely, the polar interactions are unfavourable for the binding process. A total of 14 residues were identified as greatly contributing to the binding free energy between edaravone and the Aβ42 monomer. In addition, the intra-peptide hydrophobic interactions were weakened and the salt bridge D23-K28 was interrupted by edaravone. Therefore, the conformational transition was inhibited. Our studies provide molecular-level insights into how edaravone molecules inhibit the conformational transition of the Aβ42 monomer, which may be useful for designing amyloid inhibitors.Communicated by Ramaswamy H. Sarma.