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PMID: 12237456 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Molecular dynamics simulations of alanine rich beta-sheet oligomers: Insight into amyloid formation.

Protein science : a publication of the Protein Society ·Vol. 11 ·No. 10 ·2002-10-00 ·Pages 2335-50

Ma B, Nussinov R

Abstract

The aggregation observed in protein conformational diseases is the outcome of significant new beta-sheet structure not present in the native state. Peptide model systems have been useful in studies of fibril aggregate formation. Experimentally, it was found that a short peptide AGAAAAGA is one of the most highly amyloidogenic peptides. This peptide corresponds to the Syrian hamster prion protein (ShPrP) residues 113-120. The peptide was observed to be conserved in all species for which the PrP sequence has been determined. We have simulated the stabilities of oligomeric AGAAAAGA and AAAAAAAA (A8) by molecular dynamic simulations. Oligomers of both AGAAAAGA and AAAAAAAA were found to be stable when the size is 6 to 8 (hexamer to octamer). Subsequent simulation of an additional alpha-helical AAAAAAAA placed on the A8-octamer surface has revealed molecular events related to conformational change and oligomer growth. Our study addresses both the minimal oligomeric size of an aggregate seed and the mechanism of seed growth. Our simulations of the prion-derived 8-residue amyloidogenic peptide and its variant have indicated that an octamer is stable enough to be a seed and that the driving force for stabilization is the hydrophobic effect.

MeSH Terms
Amyloid/metabolism Computer Simulation Models, Molecular Peptides/metabolism Protein Conformation Protein Structure, Secondary
Chemicals
Amyloid Peptides polyalanine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Ma Buyong
Laboratory of Experimental and Computational Biology, National Cancer Institute at Frederick, Maryland 21702, USA.
Nussinov Ruth
References (35)
35 references, click to expand
  1. Molecular biology of prion diseases.
    Science. 1991 Jun 14;252(5012):1515-22 PMID: 1675487
  2. Short peptide amyloid organization: stabilities and conformations of the islet amyloid peptide NFGAIL.
    Biophys J. 2003 Mar;84(3):1884-94 PMID: 12609890
  3. Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie?
    Cell. 1993 Jun 18;73(6):1055-8 PMID: 8513491
  4. Reversible random coil-beta-sheet transition of the Alzheimer beta-amyloid fragment (25-35).
    Biochemistry. 1994 Feb 15;33(6):1345-50 PMID: 8312252
  5. Inhibition of PC12 cell redox activity is a specific, early indicator of the mechanism of beta-amyloid-mediated cell death.
    Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1470-4 PMID: 8108433
  6. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus.
    Nature. 1994 Apr 21;368(6473):756-60 PMID: 8152488
  7. Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity.
    J Neurochem. 1995 Jan;64(1):253-65 PMID: 7798921
  8. The toxicity in vitro of beta-amyloid protein.
    Biochem J. 1995 Oct 1;311 ( Pt 1):1-16 PMID: 7575439
  9. On the nucleation and growth of amyloid beta-protein fibrils: detection of nuclei and quantitation of rate constants.
    Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1125-9 PMID: 8577726
  10. Polyalanine-based peptides as models for self-associated beta-pleated-sheet complexes.
    Biochemistry. 1997 Jul 8;36(27):8393-400 PMID: 9204887
  11. Kinetic theory of fibrillogenesis of amyloid beta-protein.
    Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7942-7 PMID: 9223292
  12. Conformational disease.
    Lancet. 1997 Jul 12;350(9071):134-8 PMID: 9228977
  13. BSE and prions: uncertainties about the agent.
    Science. 1998 Jan 2;279(5347):42-3 PMID: 9441410
  14. Design of a 20-amino acid, three-stranded beta-sheet protein.
    Science. 1998 Jul 10;281(5374):253-6 PMID: 9657719
  15. From the globular to the fibrous state: protein structure and structural conversion in amyloid formation.
    Q Rev Biophys. 1998 Feb;31(1):1-39 PMID: 9717197
  16. Prions.
    Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83 PMID: 9811807
  17. Quantifying the kinetic parameters of prion replication.
    Biophys Chem. 1999 Mar 29;77(2-3):139-52 PMID: 10326247
  18. The presenilins in Alzheimer's disease--proteolysis holds the key.
    Science. 1999 Oct 29;286(5441):916-9 PMID: 10542139
  19. Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties.
    J Mol Biol. 2000 Jan 28;295(4):1055-71 PMID: 10656810
  20. Two-dimensional structure of beta-amyloid(10-35) fibrils.
    Biochemistry. 2000 Mar 28;39(12):3491-9 PMID: 10727245
  21. Molecular dynamics simulations of a beta-hairpin fragment of protein G: balance between side-chain and backbone forces.
    J Mol Biol. 2000 Mar 3;296(4):1091-104 PMID: 10686106
  22. Intracellular green fluorescent protein-polyalanine aggregates are associated with cell death.
    Biochem J. 2000 May 15;348 Pt 1:15-9 PMID: 10794708
  23. Evidence for the prion hypothesis: induction of the yeast [PSI+] factor by in vitro- converted Sup35 protein.
    Science. 2000 Jul 28;289(5479):595-9 PMID: 10915616
  24. Inhibition of toxicity in the beta-amyloid peptide fragment beta -(25-35) using N-methylated derivatives: a general strategy to prevent amyloid formation.
    J Biol Chem. 2000 Aug 18;275(33):25109-15 PMID: 10825171
  25. Nucleated conformational conversion and the replication of conformational information by a prion determinant.
    Science. 2000 Aug 25;289(5483):1317-21 PMID: 10958771
  26. Mutational analysis of designed peptides that undergo structural transition from alpha helix to beta sheet and amyloid fibril formation.
    Structure. 2000 Sep 15;8(9):915-25 PMID: 10986459
  27. Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer's beta-amyloid peptide, and structural characterization by solid state NMR.
    Biochemistry. 2000 Nov 14;39(45):13748-59 PMID: 11076514
  28. An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated beta-sheet structure for amyloid.
    Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2375-80 PMID: 11226247
  29. Bidirectional amyloid fiber growth for a yeast prion determinant.
    Curr Biol. 2001 Mar 6;11(5):366-9 PMID: 11267875
  30. Quantification of the hydrophobic interaction by simulations of the aggregation of small hydrophobic solutes in water.
    Proc Natl Acad Sci U S A. 2001 May 22;98(11):5965-9 PMID: 11353861
  31. Self-assembly of beta-sheets into nanostructures by poly(alanine) segments incorporated in multiblock copolymers inspired by spider silk.
    J Am Chem Soc. 2001 Jun 6;123(22):5231-9 PMID: 11457385
  32. Analysis of the minimal amyloid-forming fragment of the islet amyloid polypeptide. An experimental support for the key role of the phenylalanine residue in amyloid formation.
    J Biol Chem. 2001 Sep 7;276(36):34156-61 PMID: 11445568
  33. Design and construction of an open multistranded beta-sheet polypeptide stabilized by a disulfide bridge.
    J Am Chem Soc. 2002 May 8;124(18):4987-94 PMID: 11982362
  34. Stabilities and conformations of Alzheimer's beta -amyloid peptide oligomers (Abeta 16-22, Abeta 16-35, and Abeta 10-35): Sequence effects.
    Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14126-31 PMID: 12391326
  35. Predicted alpha-helical regions of the prion protein when synthesized as peptides form amyloid.
    Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10940-4 PMID: 1438300
Article Info
Journal
Protein science : a publication of the Protein Society
Abbr.
Protein Sci
ISSN
0961-8368
DOI
10.1110/ps.4270102
Published
2002-10-00
Pages
2335-50
Language
English
Region
United States
NLM ID
9211750
PMCID
PMC2373704
Subset
IM
Grants
NCI NIH HHS · N01CO12400 · United States
NCI NIH HHS · N01-CO-12400 · United States
External Links
PubMed source DOI: 10.1110/ps.4270102 PMC Full Text View journal details
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