Amyloids and the associated aggregation and oligomer-formation process can be influenced and exacerbated by the quantity and type of other amyloid peptides present. Amyloid-beta (Aβ) and islet amyloid polypeptide (IAPP) are amyloidogenic peptides that have the potential to self-assemble and form cytotoxic species that are observed as a range from small soluble oligomers and large insoluble fibrils. This work utilizes molecular dynamics (MD) simulations to create a model system using known “hot spot” regions of Aβ and IAPP in order to study cross-amyloid hexamer interactions in a heterogeneous and homogenous peptide-containing environment. Then, full-length Aβ(42) dimer to nonamer oligomer structures were simulated. All simulation systems were constructed with all peptides separated by a distance outside of long-range interactions as to observe the process of aggregation and subsequent interaction interfaces and resulting dominant morphologies based on the number and type of peptide present. Model systems of Aβ(16-22) formed antiparallel, β-barrel-like structures, while systems of only IAPP(20-29) peptides formed stacked, parallel β-sheets and had relatively unstable aggregation structures. Systems containing both Aβ and IAPP hexamers showed antiparallel, β-barrel-like structures, with an interdigitated arrangement of Aβ(16-22) and IAPP(20-29). Full-length Aβ(42) oligomers demonstrated several morphologies and eccentricity values, including both compact and extended antiparallel β-sheet structures, with the overall size and eccentricity of the oligomers formed increasing nonlinearly. Simulations suggest that rearrangement into a fibrillar form, if on-pathway for full-length oligomers of this type, must occur as a linearizing rearrangement of oligomers that self-assemble into globular clusters while exponentially increasing in size over time. This work provides a foundational biophysical characterization and dominant morphologies of full length and model system amyloids in homogenous and heterogeneous environments, ultimately setting the stage for future exploration of in silico mutagenesis and insight into similar and unique features across these amyloids and their oligomeric structures.

Insight into amyloid interactions and aggregation processes: Molecular dynamics simulations of amyloid fragments and full-length oligomers

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.