Small Molecules as Amyloid Inhibitors: Molecular Dynamic Simulations with Human Islet Amyloid Polypeptide (IAPP)

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 co-morbidity 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 inter-peptide β-strands comprised of residues 23-27 (FGAIL). Flavonoids, a class of polyphenolic natural products, have been found experimentally to inhibit IAPP aggregate formation. Many of these known IAPP aggregation attenuating 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 (MD) simulations were performed on a model fragment of IAPP(20-29) in the presence of morin, quercetin, dihydroquercetin, epicatechin, and myricetin. Contacts between Phe23 residues are critical to oligomer formation, and small-molecule contacts with Phe23 are a key predictor of β-strand reduction. Structural properties influencing the ability of compounds to disrupt Phe23-Phe23 contacts include carbonyl and hydroxyl group placement. These structural features influence aromaticity and hydrophobicity, principally affecting ability to disrupt IAPP(20-29) oligomer formation. This work provides key information on design considerations for T2D therapeutics.

Name thesis:degree_name

Master of Science in Life Sciences

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Biochemistry

Department dc:contributor.department

Biochemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2021

Author dc:creator

• King, Kelsie Marie

Chair dc:contributor.committeechair

• Brown, Anne M.

Committee members dc:contributor.committeemember

• Helm, Richard F.
• Lemkul, Justin A.

• amyloids
• islet amyloid polypeptide
• flavonoids
• molecular dynamics simulations
• drug discovery

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:30657

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/112763