Study on the structure and membrane disruption of the peptide oligomers constructed by hIAPP18-27 peptide and its d,l-alternating isomer.

Increasing lines of evidence show that the oligomeric intermediates of amyloid peptides/proteins are toxic to biological membranes. However, the structural features of the oligomers that are closely associated with the ability to damage biological membranes are far from understanding. In this study, we constructed two species of oligomers using hIAPP18-27 peptide and its d,l-alternating isomer, examined the disruptive ability of the oligomers to POPC/POPG 4:1 vesicles by leakage assay and 31P NMR spectroscopy, and characterized the structural features of the oligomers by CD, TEM, 1H NMR and fluorescence quenching experiments. We found that the d,l-alternating peptide oligomers are more disruptive than the all-L peptide oligomers to the lipid membrane. The characterization of the secondary structure revealed that the d,l-alternating peptide adopts an extended polyproline type-II (PPII) conformation, while the all-L peptide adopts a random coil conformation in oligomers. Compared with the all-L peptide oligomers, the d,l-alternating peptide oligomers are less compact and keep more hydrophobic groups water exposed. Both the changes from PPII to α-sheet in the structure of d,l-alternating peptide and from random coil to β-sheet in the structure of all-L peptide reduce the ability of the peptide oligomers to disrupt the lipid membrane. Our results suggest that an oligomer with extended peptide chains could be more potent in membrane disruption than an oligomer with folded peptide chains and an increase in peptide-peptide interaction could decrease the disruptive ability of oligomer.