Amphiphilic Adsorption of Human Islet Amyloid Polypeptide Aggregates to Lipid/Aqueous Interfaces

Many amyloid proteins misfold into β-sheet aggregates upon interacting with biomembranes at the onset of diseases, such as Parkinson's disease and type II diabetes. The molecular mechanisms triggering aggregation depend on the orientation of β-sheets at the cell membranes. However, understanding how β-sheets adsorb onto lipid/aqueous interfaces is challenging. Here, we combine chiral sum frequency generation (SFG) spectroscopy and ab initio quantum chemistry calculations based on a divide-and-conquer strategy to characterize the orientation of human islet amyloid polypeptides (hIAPPs) at lipid/aqueous interfaces. We show that the aggregates bind with β-strands oriented at 48° relative to the interface. This orientation reflects the amphiphilic properties of hIAPP β-sheet aggregates and suggests the potential disruptive effect on membrane integrity.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (228 K)Download as PowerPoint slideHighlights► We obtain a high-resolution chiral SFG spectrum of hIAPP aggregates. ► In theory, we relate the ratio of two SFG peaks to the aggregates' orientation. ► We find four possible orientations for the hIAPP by the theory. ► We simulate the four possible SFG spectra by a new “divide-and-conquer” approach. ► By comparison, we find that the hIAPP orients at an angle of 48° at interfaces.