LAUSR

Abstract 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