An improved understanding of protein misfolding is critical to the study of proteins involved in diseases such as Alzheimers and prion-related diseases, as well as to the clarification of the folding pathway of proteins. In general, hydrophobic clustering seems to be an important feature for peptide transformation. In this study, we applied the concept of hydrophobic defect in order to design and synthesize a peptide capable of performing an a ± b structural transition. The peptide was composed of two amphiphilic a-helix segments, each modified with a 1-adamantanecarbonyl group at the N-terminal as a hydrophobic defect. The peptide folded in a 2a-helix structure at first, but the conformation changed gradually to a bstructure in neutral aqueous solution. Electron micrographs showed that the b-structural peptide formed amyloid fibrils (% 10 nm width), which were resistant to proteolytic degradation, and the fibrils assembled into larger deposits (10 ± 100 mm) observable with a light microscope. The hydrophobic association process was supported by the temperature-dependent transition and by the inhibition experiments with b-cyclodextrin, trifluoroethanol, and ionic detergents. The a ± b transition and the amyloid fibrillogenesis of the designed peptide mimic the misfolding process of amyloidogenic proteins, which may proceed along a nucleation reaction and a subsequent autocatalytic transition reaction.