Solution conformation and amyloid-like fibril formation of a polar peptide derived from a β-hairpin in the OspA single-layer β-sheet

A 23-residue peptide termed BH9–10 was designed based on a β-hairpin segment of the single-layer β-sheet region of Borrelia OspA protein. The peptide contains a large number of charged amino acid residues, and it does not follow the amphipathic pattern that is commonly found in natural β-sheets. In aqueous solution, the peptide was highly soluble and flexible, with a propensity to form a non-native β-turn. Trifluoroethanol (TFE) stabilized a native-like β-turn in BH9–10. TFE also decreased the level of solubility of the peptide, resulting in peptide precipitation. The precipitation process accompanied a conformational conversion to a β-sheet structure, as judged with circular dichroism spectroscopy. The precipitate was found to be fibrils similar to those associated with human amyloid diseases. The fibrillization kinetics depended on peptide and TFE concentrations, and had a nucleation step followed by an assembly step. The fibrillization was reversible, and the dissociation reaction involved two phases. TFE appears to induce the fibrils by stabilizing a β-sheet conformation of the peptide that optimally satisfies hydrogen bonding and electrostatic complementarity. This TFE-induced fibrillization is quite unusual, because most amyloidogenic peptides form fibrils in aqueous solution and TFE disrupts these fibrils. Nevertheless, the BH9–10 fibrils have similar structure to other fibrils, supporting the emerging idea that polypeptides possess an intrinsic ability to form amyloid-like fibrils. The high level of solubility of BH9–10, the ability to precisely control fibril formation and dissociation, and the high-resolution structure of the same sequence in the β-hairpin conformation in the OspA protein provide a tractable experimental system for studying the fibril formation mechanism.