Perturbing the conformation of diabetes-associated oligomers using molecular foldamers.

Abstract

The islet amyloid polypeptide (IAPP) is a 37 aa peptide hormone secreted from pancreatic β-cells. In patients with Type II Diabetes, IAPP undergoes a toxic gain-of-function that results in the formation of amyloid fibrils. While these fibrils are a hallmark of the disease, soluble oligomeric precursors are most potently linked with IAPP pathogenicity. IAPP oligomers (IAos) disrupt homeostasis through a variety of mechanisms, including mitochondrial stress, aberrant Ca2+ signaling, and the formation of membrane pores. However, the biophysics of IAo pathogenicity is poorly characterized due to their instability in solution. We have shown that sodium dodecyl sulfate (SDS) micelles (which mimic anionic membranes) can stabilize IAos of different sizes in a physiological buffer. However, the morphology and conformational diversity of IAPP at the lipid interface is still unclear. We hypothesize that IAo first assembles on membrane surfaces and forms oligomers, which enables misfolding and their toxic gain-of-function. To gain molecular insight into the formation of IAo at this interface, we employ replica-exchange molecular dynamics (MD) and classical MD simulations. We monitor the conformation of IAo in the presence of various protein/micelle ratios as well as in free detergent. Finally, we introduce a molecular foldamer—shown to rescue IAPP-induced toxicity in cell models—to understand its effect on its conformational landscape. By comparing accessible conformations with and without the foldamer, we hope to identify conformations stabilized by the binding interaction. Molecular foldamers demonstrate the therapeutic potency of conformational modulators towards treating IAPP toxicity in T2D. Furthermore, this general strategy can be applied to other disordered peptides (e.g. amyloid-β) that undergo pathological misfolding.