Structural Insights into the Amyloid Fibril Polymorphism Using an Isotope-Edited Vibrational Circular Dichroism Study at the Amino Acid Residue Level

Polymorphism is common in both in vitro and in vivo amyloid fibrils formed by the same peptide/protein. However, the differences in their self-assembled structures at the amino acid level remain poorly understood. In this study, we utilized isotopeedited vibrational circular dichroism (VCD) on a well-known amyloidogenic peptide fragment (N(22)FGAIL(27)) of human islet amyloid polypeptide (IAPf) to investigate the structural polymorphism. Two individual isotope-labeled IAPf peptides were used, with a C-13 label on the carbonyl group of phenylalanine (IAPf-F) and glycine (IAPf-G). We compared the amyloid-like nanofibril of IAPf induced by solvent casting (fibril B) with our previous report on the same IAPf peptide fibril but with a different fibril morphology (fibril A) formed in an aqueous buffer solution. Fibril B consisted of entangled, laterally fused amyloid-like nanofibrils with a relatively shorter diameter (15-50 nm) and longer length (several microns), while fibril A displayed nanofibrils with a higher diameter (30-60 nm) and shorter length (500 nm-2 mu m). The isotope-edited VCD analysis indicated that fibrils B consisted of anti-parallel ss-sheet arrangements with glycine residues in the registry and phenylalanine residues out of the registry, which was significantly different from fibrils A, where a mixture of parallel ss-sheet and turn structure with the registry at phenylalanine and glycine residues was observed. The VCD analysis, therefore, suggests that polymorphism in amyloid-like fibrils can be attributed to the difference in the packing/arrangement of the individual ss strands in the ss-sheet and the difference in the amino acid registry. Our findings provide insights into the structural aspects of fibril polymorphism related to various amyloid diseases and may aid in designing amyloid fibril inhibitors for therapeutic purposes.

Automated summary

This study investigated the structural polymorphism of amyloid fibrils formed by a peptide fragment using isotope-edited vibrational circular dichroism. The results showed differences in diameter, length, and β-sheet structure between two different fibril morphologies. The findings provide insights into the structural aspects of fibril polymorphism and may aid in therapeutic drug design for amyloid diseases.