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Molecular Dynamics Simulations Indicate Aromaticity as a Key Factor in the Inhibition of IAPP(20-29) Aggregation
Kelsie M King1, David R Bevan1,2, Anne M Brown1,3,2
1Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States.
ACS Chemical Neuroscience
|May 19, 2022
Summary
Flavonoids can inhibit toxic amyloid aggregation in Type II Diabetes (T2D) by disrupting key protein interactions. Specific structural features of these compounds are crucial for effective therapeutic design against T2D progression.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Islet amyloid polypeptide (IAPP) aggregation contributes to Type II Diabetes (T2D) pathogenesis by reducing pancreatic beta-cell mass.
- Toxic oligomer formation by IAPP is linked to interpeptide beta-strands within the IAPP(20-29) fragment.
- Flavonoids are natural compounds known to inhibit IAPP aggregation, but the impact of their specific structural features remains unclear.
Purpose of the Study:
- To investigate how structural variations in flavonoids influence their ability to inhibit IAPP(20-29) aggregation.
- To identify key molecular interactions and structural properties responsible for the anti-aggregation effects of flavonoids.
- To provide insights for designing novel T2D therapeutics targeting IAPP.
Main Methods:
- Molecular dynamics simulations were employed to model trimer formation of the IAPP(20-29) fragment.
- Simulations included the presence of various flavonoids: morin, quercetin, dihydroquercetin, epicatechin, and myricetin.
- Analysis focused on interpeptide contacts, particularly between Phe23 residues, and the influence of small molecules on these interactions.
Main Results:
- Phe23 residue contacts were identified as critical for IAPP oligomer formation.
- Interactions between flavonoids and Phe23 residues predicted the reduction of beta-strand formation.
- Aromaticity and the positioning of carbonyl and hydroxyl groups in flavonoids were key structural factors affecting their ability to disrupt Phe23-Phe23 contacts.
Conclusions:
- Flavonoid structural features, including aromaticity and functional group placement, significantly impact their efficacy in inhibiting IAPP aggregation.
- Disruption of Phe23-Phe23 contacts by flavonoids is a primary mechanism for preventing toxic oligomer formation.
- This study offers valuable design principles for developing small-molecule therapeutics aimed at mitigating T2D progression by targeting IAPP.
Keywords:
drug discoveryflavonoidsislet amyloid polypeptide (IAPP)molecular dynamics simulationstype II diabetes (T2D)More Related Videos
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