Oral Presentation 10th Australian Peptide Conference 2013

We have designed a new class of aliphatic peptides made of just 3-6 amino acids that self-assemble in water via α-helical intermediates to amyloid β-type fibers. While core sequences of 4-7 residues that form amyloid fibrils have been identified within natural proteins, the mechanism of aggregation remains unclear. We compared the self-assembly of our designed peptides with core sequences in Amyloid-beta, Amylin and Calcitonin using a multimodal approach. A common feature was the appearance of α-helical intermediates before the final β-turn structures. Another amyloid-beta core sequence containing the diphenylalanine motif was chosen to evaluate the role of aromatic residues in self-assembly. The repeated occurrence of aromatic residues in core sequences has led to widespread conclusions about their key role in driving self-assembly. Surprisingly, the diphenylalanine-containing sequence did not form cross-β aggregates or involve the α-helical intermediate step. Our study puts forth a new, simplified model system to study amyloidosis and indicates that aromatic interactions are not as important as previously postulated. The results provide valuable insight into the early intermediates and factors driving self-assembly, which is necessary for developing small molecule therapeutic drugs that prevent amyloidosis.