While significant progress has been made in developing approaches to study self-assembly leading to homomeric fibril formation by identical proteins, our understanding of heterotypic cross-interactions formed by different proteins is limited. Understanding such cross-interactions is key, due to their involvement in biology and their implication in health. We have developed a novel computational approach for the study of heterotypic cross-aggregates, comprising a combination of a novel in-house biased molecular dynamics simulations tool, and conventional molecular dynamics simulations. During the stage of biased molecular dynamics simulations, the structure of a heterotypic cross-interaction is modeled and refined using modified energy functions, while subsequently the cross-interacting structure is validated through state-of-the-art atomistic simulations. Our novel approach has been applied to study several cross-interaction fibrillar systems, and in this talk, we will highlight an example of its application to delineate the cross-interaction between Amyloid-beta (Aβ) and Islet Amyloid Polypeptide (IAPP) fibrils. We provide detailed thermodynamics analysis and a biophysical characterization of the structural and dynamical properties of Aβ-IAPP cross-self-assembled systems in comparison to individual assembled systems of Aβ and IAPP. Additionally, we present the role of structural transitions in enhancing cross-interactions. We consider that our novel computational approach can be used to delineate a series of cross-interacting assemblies, providing invaluable insights to the role of such interactions in biology and diseases.
