Amyloid refers to an insoluble, highly organized protein fibril composed of intermolecular β-sheets, known as a cross-β motif. Oligomeric amyloids are highly polymorphic and modulate secondary and tertiary structures in response to environmental factors. Amyloid proteins are ubiquitous across phyla, exploiting stability and storage capabilities to serve a wide range of critical functions. The unique conformational flexibility exhibited by amyloids, however, often gives rise to misfolded, cytotoxic oligomeric structures implicated in multiple diseases. Cytotoxic amyloid formation is intrinsically linked to the aggregation environment — lipid composition exerts a profound impact on the modes of cytotoxicity exhibited by amyloids. Given the implication of amyloid cytotoxicity, it is crucial to understand the influence of microenvironments on the biophysics of aggregation. Using molecular dynamics (MD) simulations, we seek to probe the impact of microenvironments on the formation of amyloid-β42 (Aβ42) and islet amyloid polypeptide (IAPP) hexamers, while seeking to comprehensively characterize various amyloidogenic morphologies in terms of structure-function relationships using cutting-edge computational techniques. Hexamer formation was simulated in the presence of various membrane compositions. Preliminary data on Aβ42 aggregation suggests that oligomers adopt distinct conformations based on aggregation microenvironment. This work gives key insights on the biophysics of amyloid aggregation in relevant environments and includes novel analysis techniques for analyzing MD simulation trajectories.

Investigating the role of microenvironment on amyloid oligomer dynamics

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