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Indexed by:期刊论文

Date of Publication:2015-06-01

Journal:10th International Conference on Chemical Structures (ICCS)/10th German Conference on Chemoinformatics (GCC)

Included Journals:SCIE、EI、CPCI-S、Scopus

Volume:55

Issue:6

Page Number:1218-1230

ISSN No.:1549-9596

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