Three dimensional models of Cu(2+)-Aβ(1-16) complexes from computational approaches
Jorge Alí-Torres1, Jean-Didier Maréchal, Luis Rodríguez-Santiago
1Departament de Química, Universitat Autònoma de Barcelona, Barcelona, Spain.
Journal of the American Chemical Society
|August 18, 2011
Summary
Understanding copper (Cu2+) coordination with amyloid-beta (Aβ) is key for Alzheimer
Area of Science:
- Biochemistry
- Computational Chemistry
- Neuroscience
Background:
- Copper ion (Cu2+) interactions with amyloid-beta (Aβ) are implicated in Alzheimer disease pathogenesis.
- Understanding the coordination of Cu2+ to Aβ is crucial for developing therapeutic chelators.
Purpose of the Study:
- To determine plausible three-dimensional models of Cu2+-Aβ(1-16) complexes.
- To investigate the coordination preferences of histidine residues and potential oxygen-containing ligands.
Main Methods:
- Combined homology modeling (HM) and quantum mechanics (QM) approaches.
- Evaluated various coordination modes for histidines (H6, H13, H14) and oxygen ligands (Asp1, Glu3, Asp7, Glu11, CO(Ala2)).
Main Results:
- Identified lowest energy structures for Cu2+-Aβ(1-16) involving specific histidine coordination and Glu3 or Asp7 as oxygen ligands.
- The most stable model with CO(Ala2) involved specific histidine coordination.
- Solvent effects may favor CO(Ala2) coordination over Glu3.
Conclusions:
- The study provides detailed structural models for Cu2+-Aβ(1-16) complexes.
- Complex stability depends on both metal coordination and peptide folding.
- Findings inform the design of chelators for Alzheimer disease treatment.
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