Dataset Information

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

ABSTRACT: Nonfibrillar neurotoxic amyloid ? (A?) oligomer structures are typically rich in ?-sheets, which could be promoted by metal ions like Zn(2+). Here, using molecular dynamics (MD) simulations, we systematically examined combinations of A?40 peptide conformations and Zn(2+) binding modes to probe the effects of secondary structure on A? 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 (?-helix and ?-hairpin) to speed dimerization and stabilize the resulting dimer. Partial ?-helices increase the dimerization speed, and dimers with ?-helix rich conformations have the lowest energy. When Zn(2+) coordinates with residues D1, H6, H13, and H14, A?40 ?-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 ?-arch dimers. However, Zn(2+)-bound ?-arch tetramers have the lowest energy. Collectively, zinc-stabilized ?-hairpin oligomers could be important in the nucleation-polymerization of cross-? structures. Our results are consistent with experimental findings that ?-helix to ?-structural transition should accompany A? aggregation in the presence of zinc ions and that Zn(2+) stabilizes nonfibrillar A? oligomers and, thus, inhibits formation of less toxic A? fibrils.

SUBMITTER: Xu L

PROVIDER: S-EPMC6407634 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar Aβ40 Peptide Oligomerization.

Xu Liang L Shan Shengsheng S Chen Yonggang Y Wang Xiaojuan X Nussinov Ruth R Ma Buyong B

Journal of chemical information and modeling 20150603 6

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 wit ...[more]

PMID: 26017140

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Project description:Human defensin 5 (HD5) is a 32-residue host-defense peptide expressed in the gastrointestinal, reproductive, and urinary tracts that has antimicrobial activity. It exhibits six cysteine residues that are regiospecifically oxidized to form three disulfide bonds (Cys(3)-Cys(31), Cys(5)-Cys(20), and Cys(10)-Cys(30)) in the oxidized form (HD5(ox)). To probe the solution structure and oligomerization properties of HD5(ox), and select mutant peptides lacking one or more disulfide bonds, NMR solution studies and analytical ultracentrifugation experiments are reported in addition to in vitro peptide stability assays. The NMR solution structure of HD5(ox), solved at pH 4.0 in 90:10 H(2)O/D(2)O, is presented (PDB: 2LXZ ). Relaxation T(1)/T(2) measurements and the rotational correlation time (τ(c)) estimated from a (15)N-TRACT experiment demonstrate that HD5(ox) is dimeric under these experimental conditions. Exchange broadening of the Hα signals in the NMR spectra suggests that residues 19-21 (Val(19)-Cys(20)-Glu(21)) contribute to the dimer interface in solution. Exchange broadening is also observed for residues 7-14 comprising the loop. Sedimentation velocity and equilibrium studies conducted in buffered aqueous solution reveal that the oligomerization state of HD5(ox) is pH-dependent. Sedimentation coefficients of ca. 1.8 S and a molecular weight of 14 363 Da were determined for HD5(ox) at pH 7.0, supporting a tetrameric form ([HD5(ox)] ≥ 30 μM). At pH 2.0, a sedimentation coefficient of ca. 1.0 S and a molecular weight of 7079 Da, corresponding to a HD5(ox) dimer, were obtained. Millimolar concentrations of NaCl, CaCl(2), and MgCl(2) have a negligible effect on the HD5(ox) sedimentation coefficients in buffered aqueous solution at neutral pH. Removal of a single disulfide bond results in a loss of peptide fold and quaternary structure. These biophysical investigations highlight the dynamic and environmentally sensitive behavior of HD5(ox) in solution, and provide important insights into HD5(ox) structure/activity relationships and the requirements for antimicrobial action.

Dataset Information

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

Publications

Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar Aβ40 Peptide Oligomerization.

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