title: Modulation of fibrillation of hIAPP core fragments by chemical modification of the peptide backbone.
abstract: The well-ordered cross β-strand structure found in amyloid aggregates is stabilized by many different side chain interactions, including hydrophobic interactions, electrostatic charge and the intrinsic propensity to form β-sheet structures. In addition to the side chains, backbone interactions are important because of the regular hydrogen-bonding pattern. β-Sheet breaking peptide analogs, such as those formed by N-methylation, interfere with the repetitive hydrogen bonding pattern of peptide strands. Here we test backbone contributions to fibril stability using analogs of the 6-10 residue fibril core of human islet amyloid polypeptide, a 37 amino acid peptide involved in the pathogenesis of type II diabetes. The Phe-Gly peptide bond has been replaced by a hydroxyethylene or a ketomethylene group and the nitrogen-atom has been methylated. In addition, we have prepared peptoids where the side chain is transferred to the nitrogen atom. The backbone turns out to be extremely sensitive to substitution, since only the minimally perturbed ketomethylene analog (where only one of the -NH- groups has been replaced by -CH(2)-) can elongate wildtype fibrils but cannot fibrillate on its own. The resulting fibrils displayed differences in both secondary structure and overall morphology. No analog could inhibit the fibrillation of the parent peptide, suggesting an inability to bind to existing fibril surfaces. In contrast, side chain mutations that left the backbone intact but increased backbone flexibility or removed stabilizing side-chain interactions had very small effect on fibrillation kinetics. We conclude that fibrillation is very sensitive to even small modifications of the peptide backbone.
authors: Center for Insoluble Protein Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Maria
authors: M
authors: Andreasen
authors: Søren B
authors: SB
authors: Nielsen
authors: Tina
authors: T
authors: Mittag
authors: Morten
authors: M
authors: Bjerring
authors: Jakob T
authors: JT
authors: Nielsen
authors: Shuai
authors: S
authors: Zhang
authors: Erik H
authors: EH
authors: Nielsen
authors: Martin
authors: M
authors: Jeppesen
authors: Gunna
authors: G
authors: Christiansen
authors: Flemming
authors: F
authors: Besenbacher
authors: Mingdong
authors: M
authors: Dong
authors: Niels Chr
authors: NC
authors: Nielsen
authors: Troels
authors: T
authors: Skrydstrup
authors: Daniel E
authors: DE
authors: Otzen
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008745:Methylation; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D034444:Peptoids / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D013057:Spectrum Analysis; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid; D004151:Dipeptides; D009842:Oligopeptides; D010446:Peptide Fragments; D034444:Peptoids; C117453:amylin (20-29); C478380:amylin (22-27); C040500:phenylalanylglycine