title: Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar Aβ40 Peptide Oligomerization.
abstract: Nonfibrillar neurotoxic amyloid β (Aβ) oligomer structures are typically rich in β-sheets, which could be promoted by metal ions like Zn(2+). Here, using molecular dynamics (MD) simulations, we systematically examined combinations of Aβ40 peptide conformations and Zn(2+) binding modes to probe the effects of secondary structure on Aβ dimerization energies and kinetics. We found that random conformations do not contribute to dimerization either thermodynamically or kinetically. Zn(2+) couples with preformed secondary structures (α-helix and β-hairpin) to speed dimerization and stabilize the resulting dimer. Partial α-helices increase the dimerization speed, and dimers with α-helix rich conformations have the lowest energy. When Zn(2+) coordinates with residues D1, H6, H13, and H14, Aβ40 β-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. Zn(2+) cannot stabilize fibril-like β-arch dimers. However, Zn(2+)-bound β-arch tetramers have the lowest energy. Collectively, zinc-stabilized β-hairpin oligomers could be important in the nucleation-polymerization of cross-β structures. Our results are consistent with experimental findings that α-helix to β-structural transition should accompany Aβ aggregation in the presence of zinc ions and that Zn(2+) stabilizes nonfibrillar Aβ oligomers and, thus, inhibits formation of less toxic Aβ fibrils.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Shengsheng
authors.initials: S
authors.lastname: Shan
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: ∥Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.|⊥Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland 21702, United States.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: ⊥Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland 21702, United States.
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D066329:Protein Aggregates; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40); D015032:Zinc