Journal article
In silico study of amyloid beta-protein folding and oligomerization
Proceedings of the National Academy of Sciences - PNAS, v 101(50), pp 17345-17350
14 Dec 2004
PMID: 15583128
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Experimental findings suggest that oligomeric forms of the amyloid beta protein (Abeta) play a critical role in Alzheimer's disease. Thus, elucidating their structure and the mechanisms of their formation is critical for developing therapeutic agents. We use discrete molecular dynamics simulations and a four-bead protein model to study oligomerization of two predominant alloforms, Abeta40 and Abeta42, at the atomic level. The four-bead model incorporates backbone hydrogen-bond interactions and amino acid-specific interactions mediated through hydrophobic and hydrophilic elements of the side chains. During the simulations we observe monomer folding and aggregation of monomers into oligomers of variable sizes. Abeta40 forms significantly more dimers than Abeta42, whereas pentamers are significantly more abundant in Abeta42 relative to Abeta40. Structure analysis reveals a turn centered at Gly-37-Gly-38 that is present in a folded Abeta42 monomer but not in a folded Abeta40 monomer and is associated with the first contacts that form during monomer folding. Our results suggest that this turn plays an important role in Abeta42 pentamer formation. Abeta pentamers have a globular structure comprising hydrophobic residues within the pentamer's core and hydrophilic N-terminal residues at the surface of the pentamer. The N termini of Abeta40 pentamers are more spatially restricted than Abeta42 pentamers. Abeta40 pentamers form a beta-strand structure involving Ala-2-Phe-4, which is absent in Abeta42 pentamers. These structural differences imply a different degree of hydrophobic core exposure between pentamers of the two alloforms, with the hydrophobic core of the Abeta42 pentamer being more exposed and thus more prone to form larger oligomers.
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Details
- Title
- In silico study of amyloid beta-protein folding and oligomerization
- Creators
- B Urbanc - Center for Polymer Studies, Department of Physics, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA. brigita@bu.eduL CruzS YunS V BuldyrevG BitanD B TeplowH E Stanley
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 101(50), pp 17345-17350
- Publisher
- PNAS; United States
- Grant note
- R01 AG018921 / NIA NIH HHS AG 18921 / NIA NIH HHS R01 NS038328 / NINDS NIH HHS NS 44147 / NINDS NIH HHS R01 NS044147 / NINDS NIH HHS NS 38328 / NINDS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000225803400008
- Scopus ID
- 2-s2.0-10644278760
- Other Identifier
- 991014878622504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology