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.