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Covalent Stabilization of Collagen Mimetic Triple Helices and Assemblies by Dopa Crosslinking

Cole, Carson C. ; Pogostin, Brett H. LU ; Cahue, Kiana A. ; Vardanyan, Vardan H. ; Bui, Thi H. ; Farsheed, Adam C. ; Swain, Joseph W.R. ; Makhoul, Jonathan T. ; Dubackic, Marija LU and Holmqvist, Peter LU , et al. (2025) In ChemBioChem 26(22).
Abstract

Creating thermally stable collagen mimetic peptides (CMPs) is a persistent challenge. Nature leverages covalent crosslinkings to stabilize collagen's signature triple helical tertiary structure and higher-order assemblies. Herein, crosslinkings between levodopa (Dopa) and lysine can covalently stabilize the triple helix in CMPs is demonstrated. Since alkaline conditions catalyze the oxidation of the catechol on Dopa to a benzoquinone, while being in proximity to the nucleophilic lysine, it is hypothesized that this reaction can be a facile method to covalently capture the supramolecular structure of CMPs by simply increasing the pH of the aqueous solvent with the addition of sodium hydroxide. This covalent capture strategy successfully... (More)

Creating thermally stable collagen mimetic peptides (CMPs) is a persistent challenge. Nature leverages covalent crosslinkings to stabilize collagen's signature triple helical tertiary structure and higher-order assemblies. Herein, crosslinkings between levodopa (Dopa) and lysine can covalently stabilize the triple helix in CMPs is demonstrated. Since alkaline conditions catalyze the oxidation of the catechol on Dopa to a benzoquinone, while being in proximity to the nucleophilic lysine, it is hypothesized that this reaction can be a facile method to covalently capture the supramolecular structure of CMPs by simply increasing the pH of the aqueous solvent with the addition of sodium hydroxide. This covalent capture strategy successfully stabilizes CMP homotrimers and a de novo designed ABC-type heterotrimer demonstrating that the Lysine-Dopa covalent bond is best templated by a supramolecular, axial cation– (Formula presented.) pairwise interaction. In nature, collagen can hierarchically assemble into fibers. This behavior can be mimicked with the self-assembly of CMPs, but the resulting nanofibers typically exhibit thermal stability below body temperature. In a final application, Dopa–Lysine covalent capture also enhances the thermal stability of CMP nanofibers well above 37 (Formula presented.) C is demonstrated. This biomimetic covalent capture strategy can stabilize a wide variety of CMP systems and potentially enable the biomedical application of these materials.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
biomimetic polymers, cation-π interactions, collagen, peptides, self-assembly
in
ChemBioChem
volume
26
issue
22
article number
e202500268
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:40607775
  • scopus:105019757331
ISSN
1439-4227
DOI
10.1002/cbic.202500268
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 Wiley-VCH GmbH.
id
4e1c685a-2505-4db9-9805-59d6d580ba7e
date added to LUP
2026-01-15 16:31:49
date last changed
2026-02-12 19:14:27
@article{4e1c685a-2505-4db9-9805-59d6d580ba7e,
  abstract     = {{<p>Creating thermally stable collagen mimetic peptides (CMPs) is a persistent challenge. Nature leverages covalent crosslinkings to stabilize collagen's signature triple helical tertiary structure and higher-order assemblies. Herein, crosslinkings between levodopa (Dopa) and lysine can covalently stabilize the triple helix in CMPs is demonstrated. Since alkaline conditions catalyze the oxidation of the catechol on Dopa to a benzoquinone, while being in proximity to the nucleophilic lysine, it is hypothesized that this reaction can be a facile method to covalently capture the supramolecular structure of CMPs by simply increasing the pH of the aqueous solvent with the addition of sodium hydroxide. This covalent capture strategy successfully stabilizes CMP homotrimers and a de novo designed ABC-type heterotrimer demonstrating that the Lysine-Dopa covalent bond is best templated by a supramolecular, axial cation– (Formula presented.) pairwise interaction. In nature, collagen can hierarchically assemble into fibers. This behavior can be mimicked with the self-assembly of CMPs, but the resulting nanofibers typically exhibit thermal stability below body temperature. In a final application, Dopa–Lysine covalent capture also enhances the thermal stability of CMP nanofibers well above 37 (Formula presented.) C is demonstrated. This biomimetic covalent capture strategy can stabilize a wide variety of CMP systems and potentially enable the biomedical application of these materials.</p>}},
  author       = {{Cole, Carson C. and Pogostin, Brett H. and Cahue, Kiana A. and Vardanyan, Vardan H. and Bui, Thi H. and Farsheed, Adam C. and Swain, Joseph W.R. and Makhoul, Jonathan T. and Dubackic, Marija and Holmqvist, Peter and Olsson, Ulf and Kolomeisky, Anatoly B. and McHugh, Kevin J. and Hartgerink, Jeffrey D.}},
  issn         = {{1439-4227}},
  keywords     = {{biomimetic polymers; cation-π interactions; collagen; peptides; self-assembly}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{22}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{ChemBioChem}},
  title        = {{Covalent Stabilization of Collagen Mimetic Triple Helices and Assemblies by Dopa Crosslinking}},
  url          = {{http://dx.doi.org/10.1002/cbic.202500268}},
  doi          = {{10.1002/cbic.202500268}},
  volume       = {{26}},
  year         = {{2025}},
}