# title
Amyloid Cross-Interactions through the Lens of Simulations: The Case of A-IAPP.

# abstract
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 A and IAPP in axial stacking. The computationally derived conformers demonstrate a high degree of compatibility in -sheet interactions and side chain contacts in the A-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 A fibril nearly as favorably as with an IAPP fibril. At least for the polymorphs examined, while both A and IAPP can adapt to each other in the junction, IAPP has a higher propensity to adopt a polymorph that is formed by homomeric A. This is in line with the notion that an A 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.

# authors[].organizations[].label
Texas A&M Engineering Experiment Station (TEES)

# keywords[]
3403 Macromolecular And Materials Chemistry

# keywords[]
Alzheimer's Disease Including Alzheimer's Disease Related Dementias (ad/adrd)

# authorList[]
Xenophontos, X., Vlachou, A., Hunt, R. K., & Tamamis, P.