Polymorphic cross-seeding amyloid assemblies of amyloid-ß and human islet amyloid polypeptide.

Epidemiological studies have shown that the development of Alzheimer's disease (AD) is associated with type 2 diabetes (T2D), but it still remains unclear how AD and T2D are connected. Heterologous cross-seeding between the causative peptides of Aß and hIAPP may represent a molecular link between AD and T2D. Here, we computationally modeled and simulated a series of cross-seeding double-layer assemblies formed by Aß and hIAPP peptides using all-atom and coarse-gained molecular dynamics (MD) simulations. The cross-seeding Aß-hIAPP assemblies showed a wide range of polymorphic structures via a combination of four ß-sheet-to-ß-sheet interfaces and two packing orientations, focusing on a comparison of different matches of ß-sheet layers. Two cross-seeding Aß-hIAPP assemblies with different interfacial ß-sheet packings exhibited high structural stability and favorable interfacial interactions in both oligomeric and fibrillar states. Both Aß-hIAPP assemblies displayed interfacial dehydration to different extents, which in turn promoted Aß-hIAPP association depending on interfacial polarity and geometry. Furthermore, computational mutagenesis studies revealed that disruption of interfacial salt bridges largely disfavor the ß-sheet-to-ß-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. This work provides atomic-level information on the cross-seeding interactions between Aß and hIAPP, which may be involved in the interplay between these two disorders.