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Biophys J. 2009 Jul 8;97(1):1-11. doi: 10.1016/j.bpj.2009.03.062.

Thermodynamic description of polymorphism in Q- and N-rich peptide aggregates revealed by atomistic simulation.

Author information

1
Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.

Abstract

Amyloid fibrils are long, helically symmetric protein aggregates that can display substantial variation (polymorphism), including alterations in twist and structure at the beta-strand and protofilament levels, even when grown under the same experimental conditions. The structural and thermodynamic origins of this behavior are not yet understood. We performed molecular-dynamics simulations to determine the thermodynamic properties of different polymorphs of the peptide GNNQQNY, modeling fibrils containing different numbers of protofilaments based on the structure of amyloid-like cross-beta crystals of this peptide. We also modeled fibrils with new orientations of the side chains, as well as a de novo designed structure based on antiparallel beta-strands. The simulations show that these polymorphs are approximately isoenergetic under a range of conditions. Structural analysis reveals a dynamic reorganization of electrostatics and hydrogen bonding in the main and side chains of the Gln and Asn residues that characterize this peptide sequence. Q/N-rich stretches are found in several amyloidogenic proteins and peptides, including the yeast prions Sup35-N and Ure2p, as well as in the human poly-Q disease proteins, including the ataxins and huntingtin. Based on our results, we propose that these residues imbue a unique structural plasticity to the amyloid fibrils that they comprise, rationalizing the ability of proteins enriched in these amino acids to form prion strains with heritable and different phenotypic traits.

PMID:
19580739
PMCID:
PMC2711369
DOI:
10.1016/j.bpj.2009.03.062
[Indexed for MEDLINE]
Free PMC Article

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