Insight into Cross-Amyloid Interactions and Morphologies: Molecular Dynamics Simulations of Model Peptide Fragments of Amyloid-β (Aβ_16-22) and Islet Amyloid Polypeptide (IAPP_20-29)

Abstract

Amyloid-beta (Aβ) and islet amyloid polypeptide (IAPP) are small peptides, classified as amyloids, that have the potential to self-assemble and form cytotoxic species, such as small soluble oligomers and large insoluble fibrils. The formation of Aβ aggregates facilitates the progression of Alzheimers disease (AD), while IAPP aggregates induce pancreatic β-cell apoptosis, leading to exacerbation of Type 2 diabetes (T2D). Cross-amyloid interactions between Aβ and IAPP have been described both in vivo and in vitro, implying the role of Aβ or IAPP as modulators of cytotoxic self-aggregation of each peptide, and suggesting that Aβ-IAPP interactions are a potential molecular link between AD and T2D. Using molecular dynamics simulations, hot spot regions of the two peptides were studied to understand the formation of hexamers in a heterogenous and homogenous peptide-containing environment. Systems of only Aβ(16-22) peptides formed antiparallel, β-barrel-like structures, while systems of only IAPP(20-29) peptides formed stacked, parallel beta strands and had relatively unstable aggregation structures after 2 µs of simulation time. Systems containing both Aβ and IAPP (1:1 ratio) hexamers showed antiparallel, β-barrel-like structures, with an interdigitated arrangement of Aβ(16-22) and IAPP(20-29). These β-barrel structures have features of cytotoxic amyloid species identified in previous literature. Ultimately, this work seeks to provide atomistic insight into both the mechanism behind cross-amyloid interactions and structural morphologies of these toxic amyloid species.