Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar A尾40 Peptide Oligomerization

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• 作者：Liang Xu ; Shengsheng Shan ; Yonggang Chen ; Xiaojuan Wang ; Ruth Nussinov ; Buyong Ma
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2015
• 出版时间：June 22, 2015
• 年：2015
• 卷：55
• 期：6
• 页码：1218-1230
• 全文大小：955K
• ISSN：1549-960X

文摘

Nonfibrillar neurotoxic amyloid 尾 (A尾) oligomer structures are typically rich in 尾-sheets, which could be promoted by metal ions like Zn²⁺. Here, using molecular dynamics (MD) simulations, we systematically examined combinations of A尾40 peptide conformations and Zn²⁺ binding modes to probe the effects of secondary structure on A尾 dimerization energies and kinetics. We found that random conformations do not contribute to dimerization either thermodynamically or kinetically. Zn²⁺ couples with preformed secondary structures (伪-helix and 尾-hairpin) to speed dimerization and stabilize the resulting dimer. Partial 伪-helices increase the dimerization speed, and dimers with 伪-helix rich conformations have the lowest energy. When Zn²⁺ coordinates with residues D1, H6, H13, and H14, A尾40 尾-hairpin monomers have the fastest dimerization speed. Dimers with experimentally observed zinc coordination (E11, H6, H13, and H14) form with slower rate but have lower energy. Zn²⁺ cannot stabilize fibril-like 尾-arch dimers. However, Zn²⁺-bound 尾-arch tetramers have the lowest energy. Collectively, zinc-stabilized 尾-hairpin oligomers could be important in the nucleation鈥損olymerization of cross-尾 structures. Our results are consistent with experimental findings that 伪-helix to 尾-structural transition should accompany A尾 aggregation in the presence of zinc ions and that Zn²⁺ stabilizes nonfibrillar A尾 oligomers and, thus, inhibits formation of less toxic A尾 fibrils.