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 Parkinsonʹs 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.