Amyloid plaques are a hallmark of many protein misfolding diseases, including type 2 diabetes mellitus (T2D). Amyloid plaques formed from amylin—a 37 amino acid peptide hormone co-secreted with insulin—have been found in patients diagnosed with T2D. In diseased patients, amylin becomes insoluble, aggregates, and forms cytotoxic amyloid deposits, ultimately leading to beta-cell death and loss of insulin production. Although T2D remains a common ailment in our population, much is left to be discovered about how these toxic aggregates form.<br/>Our research objective is to investigate the assembly pathway of amylin peptides. We simulated a system of 20 amylin peptides starting from a random coil configuration using discontinuous molecular dynamics (DMD) in conjunction with the PRIME20 force-field. Our simulation method has been used as a predictive tool to determine aggregation mechanics for homotypic and heterotypic assembly. The combination of DMD and PRIME20 allows us to characterize peptide aggregates at a microsecond timescale within a wall-clock time of a few weeks.<br/>Simulation results have identified key interactions as well as intermediate structures formed during self-assembly. We find that amylin peptides assemble into a parallel beta-structure with a hinge, in agreement with experimental evidence. The amylin peptides tend to first join at residues 20-29 followed by a conformation change to a fibril structure.  Through visualization of our results, we are also able to identify oligomeric intermediates that form before assembling into a larger structure. Interactions between amylin peptides and oligomers are driven and stabilized by hydrophobic interactions and hydrogen bond formation. Our work is the first to simulate amylin peptides at this scale and resolution without the aid of a crystallized structure. Knowledge of amylin’s assembly mechanism may be used to guide future studies of Aβ, α-synuclein, and other fibrillogenic peptides.

Identifying key interactions in amylin self-assembly via discontinuous molecular dynamics

ACS Spring 2022

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