Journal article
Insights into Formation and Structure of Aβ Oligomers Cross-Linked via Tyrosines
The journal of physical chemistry. B, v 121(22), pp 5523-5535
08 Jun 2017
PMID: 28482661
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer’s disease (AD) pathology is hypothesized to be triggered by amyloid β-protein (Aβ) assembly into oligomers. Oligomer size distributions of both predominant Aβ alloforms, Aβ40 and Aβ42, can be determined in vitro using cross-linking followed by gel electrophoresis. Cross-linking, which can occur in vivo in the presence of copper and hydrogen peroxide, was recently shown to stabilize Aβ oligomers by inhibiting their conversion into fibrils. Whereas several studies showed that cross-linking is facilitated by dityrosine bond formation, the molecular-level mechanism of cross-linking remains unclear. Here, we use efficient discrete molecular dynamics with DMD4B-HYDRA force field to examine the effect of cross-linking via tyrosines on Aβ oligomer formation. Our results show that cross-linking via tyrosines promotes Aβ self-assembly, in particular that of Aβ40, but does not account for cross-linked oligomers larger than Aβ40 trimers and Aβ42 tetramers. Cross-linking via tyrosines profoundly alters Aβ40 and Aβ42 oligomer conformations by increasing the solvent exposure of hydrophobic residues, resulting in elongated oligomeric morphologies that differ from globular structures of noncross-linked oligomers. When compared to available experimental data, our findings imply that amino acids other than tyrosines are involved in Aβ cross-linking, a proposition that is currently under investigation.
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Details
- Title
- Insights into Formation and Structure of Aβ Oligomers Cross-Linked via Tyrosines
- Creators
- Shuting Zhang - Drexel UniversityDillion M Fox - Drexel UniversityBrigita Urbanc - Drexel University
- Publication Details
- The journal of physical chemistry. B, v 121(22), pp 5523-5535
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000403191700007
- Scopus ID
- 2-s2.0-85021418940
- Other Identifier
- 991019168519804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Physical