Correlations among Morphology, β-Sheet Stability, and Molecular Structure in Prion Peptide Aggregates

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Abstract
The misfolding of proteins into β-sheets and the subsequent aggregation of these sheets into fibrous networks underlies many diseases. In this paper, the role of peptide structure in determining the ordering of β-sheet aggregates and the morphology of fibrils and protofibrils is dissected. Using a series of peptides based on residues 109−122 of the Syrian hamster prion protein (H1) with a range of substitutions at position 117, the link between side chain interactions and β-sheet thermal stability has been investigated. The thermal stability of β-sheets is associated with the peptides' ability to adopt the same alignment as wild-type H1, with residue 117 in register across all β-strands [Silva, R. A. G. D., Barber-Armstrong, W., and Decatur, S. M. (2003) J. Am. Chem. Soc.125, 13674−13675]. These aligned strands are capable of forming long, rigid, and twisted fibrils (as visualized by atomic force microscopy) which are thermostable. Peptides which do not adopt this strand alignment aggregate to form thin, flexible, and smooth protofibrils. The ability to form ordered aggregates, and thus to form twisted fibrils, is modulated by the structure of the side chain of residue 117.