Modeling the interface between islet amyloid polypeptide and insulin-based aggregation inhibitors: correlation to aggregation kinetics and membrane damage
| Autor: | Deborah L. Heyl, Joshua M. Osborne, Ranadheer Reddy Pesaru, M.C. Milletti, Hector Figueroa, Swathi Ramaraju, Durgaprasad Peddi, Brenan M. Wilson, Balakrishna Kurva |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Amyloid General Chemical Engineering medicine.medical_treatment Molecular Sequence Data Peptide Library and Information Sciences Protein Structure Secondary Protein structure medicine Humans Insulin Amino Acid Sequence chemistry.chemical_classification geography geography.geographical_feature_category Cell Membrane Proteins Fibrillogenesis General Chemistry Islet Computer Science Applications Islet Amyloid Polypeptide Kinetics Membrane chemistry Biochemistry Quantum Theory Salt bridge |
| Zdroj: | Journal of chemical information and modeling. 52(5) |
| ISSN: | 1549-960X |
| Popis: | Human islet amyloid polypeptide (hIAPP) forms cytotoxic fibrils in type-2 diabetes and insulin is known to inhibit formation of these aggregates. In this study, a series of insulin-based inhibitors were synthesized and assessed for their ability to slow aggregation and impact hIAPP-induced membrane damage. Computational studies were employed to examine the underlying mechanism of inhibition. Overall, all compounds were able to slow aggregation at sufficiently high concentrations (10× molar excess); however, only two peptides showed any inhibitory capability at the 1:1 molar ratio (EALYLV and VEALYLV). The results of density functional calculations suggest this is due to the strength of a salt bridge formed with the Arg11 side chain of hIAPP and the inhibitors' ability to span from the Arg11 to past the Phe15 residue of hIAPP, blocking one of the principal amyloidogenic regions of the molecule. Unexpectedly, slowing fibrillogenesis actually increased damage to lipid membranes, suggesting that the aggregation process itself, rather than the fibrilized peptide, may be the cause of cytotoxicity in vivo. |
| Databáze: | OpenAIRE |
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