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A multiscale approach to characterize the early aggregation steps of the amyloid-forming peptide GNNQQNY from the yeast prion sup-35

Jessica Nasica-Labouze, Massimiliano Meli, Philippe Derreumaux, Giorgio Colombo and Normand Mousseau

Article (2011)

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The self-organization of peptides into amyloidogenic oligomers is one of the key events for a wide range of molecular and degenerative diseases. Atomic-resolution characterization of the mechanisms responsible for the aggregation process and the resulting structures is thus a necessary step to improve our understanding of the determinants of these pathologies. To address this issue, we combine the accelerated sampling properties of replica exchange molecular dynamics simulations based on the OPEP coarse-grained potential with the atomic resolution description of interactions provided by all-atom MD simulations, and investigate the oligomerization process of the GNNQQNY for three system sizes: 3-mers, 12-mers and 20-mers. Results for our integrated simulations show a rich variety of structural arrangements for aggregates of all sizes. Elongated fibril-like structures can form transiently in the 20-mer case, but they are not stable and easily interconvert in more globular and disordered forms. Our extensive characterization of the intermediate structures and their physico-chemical determinants points to a high degree of polymorphism for the GNNQQNY sequence that can be reflected at the macroscopic scale. Detailed mechanisms and structures that underlie amyloid aggregation are also provided.

Uncontrolled Keywords

Amyloid/*chemistry; Molecular Dynamics Simulation; Oligopeptides/chemistry; Peptide Termination Factors/*chemistry; Prions/*chemistry; Protein Conformation; Saccharomyces cerevisiae Proteins/*chemistry

Subjects: 5000 Genetics > 5000 Genetics
Department: Department of Engineering Physics
Funders: NSERC (Natural Sciences and Engineering Research Council of Canada), Canada Research Chair Foundation, Fonds de la recherche en santé du Québec, Réseau québécois de calcul de haute performance
PolyPublie URL: https://publications.polymtl.ca/5052/
Journal Title: PLOS Computational Biology (vol. 7, no. 5)
Publisher: PLOS
DOI: 10.1371/journal.pcbi.1002051
Official URL: https://doi.org/10.1371/journal.pcbi.1002051
Date Deposited: 23 Feb 2023 13:55
Last Modified: 21 May 2023 06:24
Cite in APA 7: Nasica-Labouze, J., Meli, M., Derreumaux, P., Colombo, G., & Mousseau, N. (2011). A multiscale approach to characterize the early aggregation steps of the amyloid-forming peptide GNNQQNY from the yeast prion sup-35. PLOS Computational Biology, 7(5), e1002051 (18 pages). https://doi.org/10.1371/journal.pcbi.1002051


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