Islet amyloid polypeptide (IAPP) is a 37-residue amyloidogenic hormone implicated in the progression of Type II Diabetes (T2D). T2D affects an estimated 422 million people yearly and is a comorbidity with numerous diseases. IAPP forms toxic oligomers and amyloid fibrils that reduce pancreatic β-cell mass and exacerbate the T2D disease state. Toxic oligomer formation is attributed, in part, to the formation of interpeptide β-strands comprised of residues 20–29 (IAPP(20–29)). Flavonoids, a class of polyphenolic natural products, have been found experimentally to inhibit IAPP aggregate formation. Many of these small flavonoids differ structurally only slightly; the influence of functional group placement on inhibiting the aggregation of the IAPP(20–29) has yet to be explored. To probe the role of small-molecule structural features that impede IAPP aggregation, molecular dynamics simulations were performed to observe trimer formation on a model fragment of IAPP(20–29) in the presence of morin, quercetin, dihydroquercetin, epicatechin, and myricetin. Contacts between Phe23 residues were critical to oligomer formation, and small-molecule contacts with Phe23 were a key predictor of β-strand reduction. Structural properties influencing the ability of compounds to disrupt Phe23–Phe23 contacts included aromaticity and carbonyl and hydroxyl group placement. This work provides key information on design considerations for T2D therapeutics that target IAPP aggregation.

Amyloids are a subset of intrinsically disordered proteins (IDPs) that self-assemble into cross-[Formula: see text] oligomers and fibrils. The structural plasticity of amyloids leads to sampling of metastable, low-molecular-weight oligomers that contribute to cytotoxicity. Of interest are amyloid-[Formula: see text] (A[Formula: see text] and islet amyloid polypeptide (IAPP), which are involved in the pathology of Alzheimer’s disease and Type 2 diabetes mellitus, respectively. In addition to forming homogenous oligomers and fibrils, these species have been found to cross-aggregate in heterogeneous structures. Biophysical properties, including electronic effects, that are unique or conserved between homogenous and heterogeneous amyloids oligomers are thus far unexplored. Here, we simulated homogenous and heterogeneous amyloid oligomers of A[Formula: see text] and IAPP[Formula: see text] fragments using the Drude oscillator model to investigate the impact of electronic polarization on the structural morphology and stability of preformed hexamers. Upon simulation of preformed, [Formula: see text]-strand rich oligomers with Drude, structural rearrangement occurred causing some loss of [Formula: see text]-strand structure in favor of random coil content for all oligomers. Homogenous A[Formula: see text] was the most stable system, deriving stability from low polarization in hydrophobic residues and through salt bridge formation. Changes in polarization were observed primarily for A[Formula: see text] residues in heterogeneous cross-amyloid systems, displaying a decrease in charged residue dipole moments and an increase in hydrophobic sidechain dipole moments. This work is the first study utilizing the Drude-2019 force field with amyloid oligomers, providing insight into the impact of electronic effects on oligomer structure and highlighting the importance of different microenvironments on amyloid oligomer stability.

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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.

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