Molecular Dynamics Simulations Indicate Aromaticity as a Key Factor in the Inhibition of IAPP(20–29) Aggregation

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.