Journal
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 18, Issue 18, Pages 12582-12591Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6cp01014h
Keywords
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Funding
- NSF of China [11274075]
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Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-beta (A beta) peptides into beta-sheet enriched fibrillar aggregates. A beta dimers formed in the initial step of A beta aggregation were reported to be the smallest toxic species. Inhibiting the formation of beta-sheet-rich oligomers and fibrils is considered as the primary therapeutic strategy for AD. Previous studies reported that fullerene derivatives strongly inhibit A beta fibrillation. However, the underlying inhibitory mechanism remains elusive. As a first step to understand fullerene-modulated full-length A beta aggregation, we investigated the conformational ensemble of the A beta 1-42 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 A beta 1-42 dimer, conformations containing diverse extended b-hairpins are also populated. The first most-populated beta-hairpins involving residues L17-D23 and A30-V36 strongly resemble the engineered b-hairpin which is a building block of toxic A beta oligomers. We find that the interaction of DMFs with A beta peptides greatly impedes the formation of such beta-hairpins and inter-peptide beta-sheets. Binding energy analyses demonstrate that DMF preferentially binds not only to the central hydrophobic motif LVFFA of the A beta 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 A beta 1-42 aggregation by fullerenes, providing theoretical insights into the development of drug candidates against AD.
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