Pathway complexity of Alzheimer's beta-amyloid Abeta16-22 peptide assembly

Structure
Sébastien SantiniPhilippe Derreumaux

Abstract

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.

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Citations

May 25, 2005·The Journal of Chemical Physics·Adrien MelquiondPhilippe Derreumaux
Mar 5, 2014·Langmuir : the ACS Journal of Surfaces and Colloids·Dongdong LinXinju Yang
Jun 1, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hui-Hsu Gavin TsaiRuth Nussinov
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Jan 19, 2007·The Journal of Chemical Physics·Philippe Derreumaux, Normand Mousseau
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