(569a) Structures of Human Amylin In the Presence of Lipid Bilayers

Type II diabetes is highly correlated to the formation of amyloid fibrils in pancreatic β-cells. These fibrils form from misfolded aggregates of human Islet Amyloid Polypeptide (hIAPP), a 37-residue polypeptide produced in conjunction with insulin. Experimental studies have shown that the presence of negatively charged lipid bilayers catalyzes the formation of these fibrils. In addition, numerous experiments suggest that cell death due to membrane leakage results from small intermediates that arise during the aggregation process rather than from the mature fibrils. Understanding the interaction of the hIAPP monomer with lipid bilayers is therefore an important first step towards understanding the origins of type II diabetes. Advanced sampling simulations were conducted to sample configurations of the protein in bulk water and in the vicinity of bilayer membranes. Previous results from our lab indicate that hIAPP forms three structures in solution: an α-helix, a β-hairpin, and a random coil. However, in the presence of a membrane, our results suggest that only two conformations are favorable: a β-hairpin similar to the one found in free solution, and a small α-helix that inserts into the membrane while a β-hairpin remains anchored to the interface. These results are consistent with recent 2D IR experimental observations from our group, and support the hypothesis that initial aggregates contain significant β-hairpin content. KQH acknowledges the support of NLM training grant 5T15LM007359.