Interpreting the aggregation kinetics of amyloid peptides

TitleInterpreting the aggregation kinetics of amyloid peptides
Publication TypeJournal Article
Year of Publication2006
AuthorsPellarin R., Caflisch A.
JournalJournal of Molecular Biology
Volume360
Issue4
Pagination882-892
Date Published2006 Jul 21
Type of ArticleResearch Article
ISSN0022-2836
KeywordsAmyloid, Amyloid beta-Peptides, Kinetics, Peptides, Protein Structure, Quaternary, Thermodynamics
Abstract

Amyloid fibrils are insoluble mainly β-sheet aggregates of proteins or peptides. The multi-step process of amyloid aggregation is one of the major research topics in structural biology and biophysics because of its relevance in protein misfolding diseases like Alzheimer's, Parkinson's, Creutzfeld-Jacob's, and type II diabetes. Yet, the detailed mechanism of oligomer formation and the influence of protein stability on the aggregation kinetics are still matters of debate. Here a coarse-grained model of an amphipathic polypeptide, characterized by a free energy profile with distinct amyloid-competent (i.e. β-prone) and amyloid-protected states, is used to investigate the kinetics of aggregation and the pathways of fibril formation. The simulation results suggest that by simply increasing the relative stability of the β-prone state of the polypeptide, disordered aggregation changes into fibrillogenesis with the presence of oligomeric on-pathway intermediates, and finally without intermediates in the case of a very stable β-prone state. The minimal-size aggregate able to form a fibril is generated by collisions of oligomers or monomers for polypeptides with unstable or stable β-prone state, respectively. The simulation results provide a basis for understanding the wide range of amyloid-aggregation mechanisms observed in peptides and proteins. Moreover, they allow us to interpret at a molecular level the much faster kinetics of assembly of a recently discovered functional amyloid with respect to the very slow pathological aggregation.

DOI10.1016/j.jmb.2006.05.033
pubindex

0079

Alternate JournalJ. Mol. Biol.
PubMed ID16797587
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