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J. Gsponer; U. Haberthür; A. Caflisch

Journal: Proc. Natl. Acad. Sci. U.S.A.
Year: 2003
Volume: 100
Issue: 9
Pages: 5154-5159
DOI: 10.1073/pnas.0835307100
Type of Publication: Journal Article

Alanine; Amino Acid Sequence; Amino Acid Substitution; Amyloid; Fungal Proteins; Peptide Termination Factors; Prions; Protein Conformation; Saccharomyces cerevisiae Proteins; Tyrosine


Understanding the early steps of aggregation at atomic detail might be crucial for the rational design of therapeutics preventing diseases associated with amyloid deposits. In this paper, aggregation of the heptapeptide GNNQQNY, from the N-terminal prion-determining domain of the yeast protein Sup35, was studied by 20 molecular dynamics runs for a total simulation time of 20 μs. The simulations generate in-register parallel packing of GNNQQNY β-strands that is consistent with x-ray diffraction and Fourier transform infrared data. The statistically preferred aggregation pathway does not correspond to a purely downhill profile of the energy surface because of the presence of enthalpic barriers that originate from out-of-register interactions. The parallel β-sheet arrangement is favored over the antiparallel because of side-chain contacts; in particular, stacking interactions of the tyrosine rings and hydrogen bonds between amide groups. No ordered aggregation was found in control simulations with the mutant sequence SQNGNQQRG in accord with experimental data and the strong sequence dependence of aggregation.