Interactions of a Water-Soluble Fullerene Derivative with Amyloid-尾 Protofibrils: Dynamics, Binding Mechanism, and the Resulting Salt-Bridge Disruption
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- 作者：Xiaoying Zhou ; Wenhui Xi ; Yin Luo ; Siqin Cao ; Guanghong Wei
- 刊名：Journal of Physical Chemistry B
- 出版年：2014
- 出版时间：June 19, 2014
- 年：2014
- 卷：118
- 期：24
- 页码：6733-6741
- 全文大小：497K
- 年卷期：v.118,no.24(June 19, 2014)
- ISSN：1520-5207
文摘
Alzheimer鈥檚 disease (AD) is associated with the pathological self-assembly of amyloid-尾 (A尾) peptides into 尾-sheet-rich oligomers and insoluble amyloid fibrils. Experimental studies reported that 1,2-(dimethoxymethano)fullerene (DMF), a water-soluble fullerene derivative, inhibits strongly A尾 peptide aggregation at the early stage. However, the interaction and binding mechanisms are not well understood. In this study, we have investigated the detailed interaction of a DMF molecule with a fibrillar hexamer of full-length A尾42 and the resulting structural alterations by performing multiple all-atom explicit solvent molecular dynamics (MD) simulations. Starting from different initial states with a minimum distance of 2 nm between the DMF and the A尾 protofibril, our MD simulations show that the DMF binds to the A尾 protofibril via both slow and fast binding processes. Three dominant binding sites are identified: the central hydrophobic core (CHC) site (17LVFFA21), the turn site (27NKGAI31), and the C-terminal 尾-sheet site consisting of the smallest side-chain residue glycine and hydrophobic residues (31IIGLMVGGVVI41). Binding energy analyses reveal the importance of 蟺-stacking interactions, especially in the CHC site, hydrophobic interactions, and curvature matching. Strikingly, we find that the binding of DMF to the turn region can disrupt the D23鈥揔28 salt-bridge that is important for the A尾 fibrillation. These results provide molecular insight into the binding mechanism of fullerene to A尾 protofibrils and offer new routes for the therapeutic drug design using fullerene derivatives against AD.