期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 38, 期 8, 页码 2377-2388出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2019.1632225
关键词
Alzheimer's disease; amyloid-beta protein; molecular dynamics simulation; edaravone; MM-PBSA method
Previous work has shown that edaravone inhibits fibrillogenesis of amyloid-beta protein (A beta). However, the detailed mechanism by which edaravone inhibits the conformational transition of the A beta 42 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 A beta 42 monomer in a dose-dependent manner. It was found that the direct interactions between edaravone and A beta 42 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 A beta 42 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 A beta 42 monomer, which may be useful for designing amyloid inhibitors. Communicated by Ramaswamy H. Sarma
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