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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Inhibition of Amyloid Formation in Model PeptidesEnrico Brandenburg 1 , Hans v. Berlepsch 2 , and Beate Koksch 11 Organische Chemie, Institut für Chemie und Biochemie, Freie Universität Berlin,Takustraße 3, 14195, Berlin, Germany; 2 Forschungszentrum für Elektronenmikroskopie,Institut für Chemie und Biochemie, Freie Universität Berlin, Fabeckstraße 36a, 14195,Berlin, GermanyIntroductionMany neurodegenerative diseases such as Alzheimer’s disease, type II diabetes,Parkinson’s disease and Creutzfeldt-Jacob disease, are associated with failure of a peptideor protein to adopt, or remain in, its functional conformational state. Often, these undergo aconformational change from the native and mainly unfolded or particularly helically foldedstate into β-sheet rich, insoluble and fibrillar assemblies, that have a characteristic cross-βstructure.We present the inhibition of amyloid formation in two de novo designed modelpeptides by a third de novo designed α-helical ideal coiled coil peptide. The design of allthree peptides is based on the naturally occurring coiled coil folding motif in which a 26residue primary sequence is characterized by a periodicity of seven residues (heptadrepeat), commonly denoted a to g [1,2].Results and DiscussionBy introducing only a few changes to the primary sequence of an ideal coiled-coil modelpeptide we were able to access a subset of model peptides having dramatically differentbehaviours. Peptide A forms a stable coiled coil with itself at neutral pH and works as aninhibitor of conformational change. The incorporation of three valine residues as β-sheetinducing features leads to peptide B which undergoes a conformational change at neutralpH from an α-helical coiled coil to a β-sheet rich amyloid-like fibril with a twisted ribbonlikemorphology. In contrast, the additional presence of lysine residues in peptide C resultsin a large positively charged domain which destabilizes the α-helical coiled coil. ThisFig. 1. Helical wheel diagram of the model peptides A, B and C.Fig. 2. (a) ThT assay of non-seeded peptide B and (b) seeded peptide B at pH 7.4 afterdifferent incubation times and for different equivalents of A (100µM B, 10µM ThT).304