Modulation of fibrillation of hIAPP core fragments by chemical modification of the peptide backbone

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Modulation of fibrillation of hIAPP core fragments by chemical modification of the peptide backbone. / Andreasen, Maria; Nielsen, Søren Bang; Mittag, Tina; Bjerring, Morten; Nielsen, Jakob T; Zhang, Shuai; Nielsen, Erik H; Jeppesen, Martin; Christiansen, Gunna; Besenbacher, Flemming; Dong, Mingdong; Nielsen, Niels Christian; Skrydstrup, Troels; Otzen, Daniel E.

In: B B A - Proteins and Proteomics, Vol. 1824, No. 2, 2012, p. 274-85.

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Andreasen, Maria ; Nielsen, Søren Bang ; Mittag, Tina ; Bjerring, Morten ; Nielsen, Jakob T ; Zhang, Shuai ; Nielsen, Erik H ; Jeppesen, Martin ; Christiansen, Gunna ; Besenbacher, Flemming ; Dong, Mingdong ; Nielsen, Niels Christian ; Skrydstrup, Troels ; Otzen, Daniel E. / Modulation of fibrillation of hIAPP core fragments by chemical modification of the peptide backbone. In: B B A - Proteins and Proteomics. 2012 ; Vol. 1824, No. 2. pp. 274-85.

Bibtex

@article{80d301f43d9544c39ee6075bed094593,
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 The Phe-Gly peptide bond has been replaced by a hydroxyethylene or a ketomethylene group and the nitrogen-atom has been methylated.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to substitution, since only the minimally perturbed ketomethylene analog (where only one of the -NH- groups has been replaced by -CH(2)-) can elongate wildtype fibrils but cannot fibrillate on its own.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.",
author = "Maria Andreasen and Nielsen, {S{\o}ren Bang} and Tina Mittag and Morten Bjerring and Nielsen, {Jakob T} and Shuai Zhang and Nielsen, {Erik H} and Martin Jeppesen and Gunna Christiansen and Flemming Besenbacher and Mingdong Dong and Nielsen, {Niels Christian} and Troels Skrydstrup and Otzen, {Daniel E}",
note = "Copyright {\circledC} 2011 Elsevier B.V. All rights reserved.",
year = "2012",
doi = "10.1016/j.bbapap.2011.10.014",
language = "English",
volume = "1824",
pages = "274--85",
journal = "B B A - Proteins and Proteomics",
issn = "1570-9639",
publisher = "Elsevier BV",
number = "2",

}

RIS

TY - JOUR

T1 - Modulation of fibrillation of hIAPP core fragments by chemical modification of the peptide backbone

AU - Andreasen, Maria

AU - Nielsen, Søren Bang

AU - Mittag, Tina

AU - Bjerring, Morten

AU - Nielsen, Jakob T

AU - Zhang, Shuai

AU - Nielsen, Erik H

AU - Jeppesen, Martin

AU - Christiansen, Gunna

AU - Besenbacher, Flemming

AU - Dong, Mingdong

AU - Nielsen, Niels Christian

AU - Skrydstrup, Troels

AU - Otzen, Daniel E

N1 - Copyright © 2011 Elsevier B.V. All rights reserved.

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1016/j.bbapap.2011.10.014

DO - 10.1016/j.bbapap.2011.10.014

M3 - Journal article

VL - 1824

SP - 274

EP - 285

JO - B B A - Proteins and Proteomics

JF - B B A - Proteins and Proteomics

SN - 1570-9639

IS - 2

ER -