Distinguishing islet amyloid polypeptide fibril structures with infrared isotope-label spectroscopy

Here, we performed spectral simulations of the amide-I vibrational spectra for three proposed fibril structures of the human islet amyloid polypeptide, which is involved in type II diabetes. We modeled both the overall absorption and two-dimensional infrared spectra for these structures. We further analyzed the isotope-labeled spectra, including the variation between structures. The analysis suggests that the infrared spectra of the cryo-electron microscopy structure provide the best match with experimental data. We further simulated isotope-labeled dilution spectroscopy investigating the correlation between the predicted spectral peak shift and the coupling between the amide units. While this correlation works in most cases, failures were observed when the isotope-labeled spectra were broad compared to the coupling or exhibited structure. These findings will be useful in the quest for potential toxic fibril formation intermediates.

Automated summary

In this study, we simulated the vibrational spectra of three proposed fibril structures of the human islet amyloid polypeptide and analyzed the isotope-labeled spectra. The results showed that the cryo-electron microscopy structure had the best match with experimental data. Additionally, the study found that failures in predicting spectral peak shifts may occur when the isotope-labeled spectra are broad compared to the coupling or exhibited structure. These findings are important for the search of potential toxic fibril formation intermediates.