Amphiphilic adsorption of human islet amyloid polypeptide aggregates to lipid/aqueous interfaces.

ABSTRACT

Many amyloid proteins misfold into ß-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 ß-sheets at the cell membranes. However, understanding how ß-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 ß-strands oriented at 48° relative to the interface. This orientation reflects the amphiphilic properties of hIAPP ß-sheet aggregates and suggests the potential disruptive effect on membrane integrity.