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

Abstract

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.

Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation

“…The side chain interactions between hydrophilic residues are also slightly reduced. The aromatic stacking involving F23 and hydrophobic interactions involving L27 were reported to be critical in hIAPP aggregation and the maintenance of structural stability for hIAPP fibrils [ 30 , 45 , 46 , 47 ]. Our results further support these points and show that Mel can greatly interfere with the aromatic stacking and hydrophobic interactions in hIAPP 20–29 association, which destabilizes and remodels the oligomers to facilitate amyloid inhibition.…”

“…The PDF of the centroid distance ( d π–π ) between the pairwise rings of the F23 residues without/with Mel shows that the peak position increases from 0.48 to 0.58 nm in the presence of Mel rather than isolated in the hIAPP 20–29 system, and the peak value drops by almost half. A previous nuclear magnetic resonance (NMR) study on tea catechins and hIAPP 22−27 and MD study on flavonoids and hIAPP 20–29 proved that aromatic stacking is vital in binding and inhibition [ 45 , 47 ]. Considering the critical role of F23 in the fibril formation and amyloid inhibition of hIAPP [ 22 , 30 , 45 ], the disruption of the F23–F23 aromatic stacking interaction induced by Mel is supposed to greatly prevent hIAPP aggregation.…”

“…A previous nuclear magnetic resonance (NMR) study on tea catechins and hIAPP 22−27 and MD study on flavonoids and hIAPP 20–29 proved that aromatic stacking is vital in binding and inhibition [ 45 , 47 ]. Considering the critical role of F23 in the fibril formation and amyloid inhibition of hIAPP [ 22 , 30 , 45 ], the disruption of the F23–F23 aromatic stacking interaction induced by Mel is supposed to greatly prevent hIAPP aggregation.…”

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

“…Since hydrophobic and hydrogen-bonding interactions between the peptides stabilize the peptide assembly, interruption of these interactions destabilizes peptide aggregation. The aromatic interactions between the aromatic amino acid residues, especially phenylalanine, are most crucial for the stabilization of amyloid aggregation . This is manifested in the fact that the central hydrophobic core of both Aβ and hIAPP, which is the amyloid-prone region, contains phenylalanine residues.…”

Disparate Effect of Hybrid Peptidomimetics Containing Isomers of Aminobenzoic Acid on hIAPP Aggregation

“…The hIAPP−BSBHp interaction is dominated by F2, p3, A4, and p5 residues of double substituted δ-BSBHp (Figure S16 of the Supporting Information), which preferentially interact with the amyloid-prone region of hIAPP, Ser19- The interaction between Phe23 residues aids in the oligomerization of hIAPP, and hence, contact between this residue and inhibitors is crucial for β-sheet reduction. 114,115 Therefore, the aromatic stacking pattern between the aromatic ring of F2 and the aminobenzoic acid (Abz) residues in the BSBHps with that of Phe15 and Phe23 residues of hIAPP is further investigated. In Figure 9, we observe that perpendicular π−π stacking is the most dominant in all stacking pairs for the system containing single substituted β-BSBHps.…”