Amyloid Cross-Interactions through the Lens of Simulations: The Case of Aβ-IAPP

While significant progress has been made in developing approaches to study amyloid self-assembly leading to homomeric fibril formation by identical proteins, our understanding of heteromeric cross-interactions formed by different proteins is limited. Understanding such cross-interactions, resulting from cross-seeding and/or coaggregation, is undeniably key due to their occurrence in biology and their implication in diseases. We have developed a new computational approach for the study of heteromeric amyloid cross-interactions in axial stacking, biased molecular dynamics (MD) simulations, followed by conventional MD simulations. The biased MD can mimic, facilitate, and accelerate the cross-interaction process, allowing the cross-interacting entities to adapt their conformations and interactions with each other. Our approach has been applied to delineate the amyloid cross-interactions that can be formed by Aβ and IAPP in axial stacking. The computationally derived conformers demonstrate a high degree of compatibility in β-sheet interactions and side chain contacts in the Aβ-IAPP cross-interaction and beyond, forming an amyloid steric zipper nearly throughout the structure. Our results depict that IAPP in the junction can cross-interact intermolecularly with an Aβ fibril nearly as favorably as with an IAPP fibril. At least for the polymorphs examined, while both Aβ and IAPP can adapt to each other in the junction, IAPP has a higher propensity to adopt a polymorph that is formed by homomeric Aβ. This is in line with the notion that an Aβ fibril can be a seed for IAPP. We suggest that the capacity of amyloids to adopt different polymorphs and the types of polymorphs they can adopt determine and drive their cross-interacting capacities; this is valid at least for the cross-interaction investigated here and could hold for other amyloid cross-interactions in general.