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The inhibitory mechanism of a fullerene derivative against amyloid-ß peptide aggregation: an atomistic simulation study.
Sun, Yunxiang; Qian, Zhenyu; Wei, Guanghong.
Afiliação
  • Sun Y; State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), and Department of Physics, Fudan University, 220 Handan Road, Shanghai, 200433, China. ghwei@fudan.edu.cn.
Phys Chem Chem Phys ; 18(18): 12582-91, 2016 05 14.
Article em En | MEDLINE | ID: mdl-27091578
Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-ß (Aß) peptides into ß-sheet enriched fibrillar aggregates. Aß dimers formed in the initial step of Aß aggregation were reported to be the smallest toxic species. Inhibiting the formation of ß-sheet-rich oligomers and fibrils is considered as the primary therapeutic strategy for AD. Previous studies reported that fullerene derivatives strongly inhibit Aß fibrillation. However, the underlying inhibitory mechanism remains elusive. As a first step to understand fullerene-modulated full-length Aß aggregation, we investigated the conformational ensemble of the Aß1-42 dimer with and without 1,2-(dimethoxymethano)fullerene (DMF) - a more water-soluble fullerene derivative - by performing a 340 ns explicit-solvent replica exchange molecular dynamics simulation. Our simulations show that although disordered states are the most abundant conformations of the Aß1-42 dimer, conformations containing diverse extended ß-hairpins are also populated. The first most-populated ß-hairpins involving residues L17-D23 and A30-V36 strongly resemble the engineered ß-hairpin which is a building block of toxic Aß oligomers. We find that the interaction of DMFs with Aß peptides greatly impedes the formation of such ß-hairpins and inter-peptide ß-sheets. Binding energy analyses demonstrate that DMF preferentially binds not only to the central hydrophobic motif LVFFA of the Aß peptide as suggested experimentally, but also to the aromatic residues including F4 and Y10 and the C-terminal hydrophobic region I31-V40. This study reveals a complete picture of the inhibitory mechanism of full-length Aß1-42 aggregation by fullerenes, providing theoretical insights into the development of drug candidates against AD.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article