Structural and energetic insight into the cross-seeding amyloid assemblies of human IAPP and rat IAPP.

The misfolding and aggregation of human islet amyloid polypeptide (hIAPP or amylin) into small oligomers and large amyloid fibrils is believed to be responsible for the dysfunction and death of pancreatic β-cells in diabetes type II. However, rat IAPP (rIAPP), which differs from the hIAPP by only 6 of 37 residues, lacks the ability to form amyloid fibrils and to induce cell death. Little is known about the cross-sequence interactions and cross-seeding structures between hIAPP and rIAPP peptides. Herein using explicit-solvent molecular dynamics (MD) simulations, we modeled and simulated different heteroassemblies formed by the amyloidogenic hIAPP and the nonamyloidogenic rIAPP peptides. Simulations showed that the U-shaped hIAPP monomer and oligomers can interact with conformationally similar rIAPP to form stable complexes and to coassemble into heterogeneous structures. Stable heterointeractions between hIAPP and rIAPP were shown to arise from hydrophobic contacts and hydrogen bonds at the interface, particularly at N- and C-terminal β-sheet regions. Because of the enhanced interpeptide interactions at the interface, upon binding to hIAPP oligomers, the β-sheet population of rIAPP was greatly increased as compared to that of rIAPP alone. More importantly, the conformational energies of rIAPP monomers at the bound state were observed to be consistently higher than those of rIAPP monomers at the unbound state. However, rIAPP monomers enable one to adopt different conformations and follow different pathways for associating with hIAPP from the high energy of the bound state to the low energy of the unbound state, without encountering any large and abrupt energy barrier. In parallel, AFM study of cross-aggregation of hIAPP and rIAPP provided additional evidence that hIAPP can seed with rIAPP to form hybrid fibrils at all concentrations similar to pure hIAPP fibrils. This work demonstrates the existence of cross-interactions between the two different IAPP peptides, which provides an improved fundamental understanding of the cross-seeding of different amyloid sequences toward amyloid aggregation and toxicity mechanisms.