Pathway complexity of Alzheimer's beta-amyloid Abeta16-22 peptide assembly.
Recent studies suggest that both soluble oligomers and insoluble fibrils have toxic effects in cell cultures, raising the interest in determining the first steps of the assembly process. We have determined the aggregation mechanisms of Abeta(16-22) dimer using the activation-relaxation technique and an approximate free energy model. Consistent with the NMR solid-state analysis, the dimer is predicted to prefer an antiparallel beta sheet structure with the expected registry of intermolecular hydrogen bonds. The simulations, however, locate three other antiparallel minima with nonnative beta sheet registries and one parallel beta sheet structure, slightly destabilized with respect to the ground state. This result is significant because it can explain the observed dependency of beta sheet registry on pH conditions. We also find that assembly of Abeta(16-22) into dimers follows multiple routes, but alpha-helical intermediates are not obligatory. This indicates that destabilization of alpha-helical intermediates is unlikely to abolish oligomerization of Abeta peptides.
Santini
Sébastien
S
Information Génomique et Structurale, CNRS UPR 2589, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.
Wei
Guanghong
G
Mousseau
Normand
N
Derreumaux
Philippe
P
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides