γ‐Azaproline Confers pH Responsiveness and Functionalizability on Collagen Triple Helices

Aronoff, Matthew R.; Egli, Jasmine; Menichelli, Massimiliano; Wennemers, Helma

doi:10.1002/ange.201813048

Cited by 8 publications

(3 citation statements)

References 61 publications

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“…1,18,19 Therefore, we have started studying the water/collagen interaction before and after Pro hydroxylation. Finally, the approach presented here can be used side by side with experimental collagen investigations, 22,[58][59][60][61][62][63][64] as complementary, reliable, accurate and parameter-free methodology.…”

Section: Discussionmentioning

confidence: 99%

Decoding Collagen Triple Helix Stability by Means of Hybrid DFT Simulations

2019

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Collagen is a protein family defined by a triple helix motif, which comprises roughly one-third of the total human protein content. Decoding the reasons underlying the stability of the collagen triple helix is of both fundamental and applicative relevance, for instance, to guide collagen protein engineering. In principle, full quantum mechanical approaches based on density functional theory (DFT) are ideal to study the subtle physico-chemical features of collagen. Unfortunately, the huge size of the protein prevents the straightforward application of DFT to realistic collagen protein models. In this paper, we propose a new realistic model of the collagen protein based on a periodic approach. The protein model exploits the intrinsic symmetry of the collagen triple helix, dramatically lowering the cost of the simulations. This allows using accurate hybrid DFT simulations (B3LYP-D/TZP) for systematic studies of the collagen protein features. We have tested the proposed model/level-of-theory combination to analyze the well-known proline-conformation/collagen-stability relationship. For this purpose, we have performed an extensive conformational analysis of proline ring within the protein, clarifying some of the reasons linking specific ring conformations to helix positions. Throughout our data analysis, we have also obtained "for free" the collagen inter-strand binding energy. Simulation results demonstrate that London dispersion interactions play the dominant role in the whole helix stability. The good agreement with the experimental data validates the use of the proposed model/level-of-theory to assist the active field of collagen-like peptide synthesis.

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Section: Discussionmentioning

confidence: 99%

Decoding Collagen Triple Helix Stability by Means of Hybrid DFT Simulations

2019

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“…In the past decades, a variety of 4 R ‐ and 4 S ‐proline derivatives have been incorporated into either the X position or the Y position within X–Y–Gly triads to explore the consequences of their pucker preference on collagen conformation (Bretscher et al, 2001; Doi et al, 2003; Hodges & Raines, 2003; Inouye et al, 1982; Kotch et al, 2008; Shoulders, Kotch, et al, 2010). In additional to applying the 4 R ‐ and 4 S ‐proline derivatives to adjust the needs of the triple helical environment, γ‐azaproline, the nitrogen analog of Thp, was also used to probe the pH‐responsiveness on collagen triple helices (Aronoff et al, 2019, 2020). Surprisingly, no studies have been reported to use the proline analog, Thp, as a substituent in CMPs to examine its impacts on a collagen triple helix.…”

Section: Introductionmentioning

confidence: 99%

Consequences of incorporating thiaproline and its oxidized derivatives into collagen triple helices

Hsu

Horng

2023

Protein Science

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2R)-4-thiaproline (Thp) is an analog of proline, replacing C γ in the pyrrolidine ring with sulfur. Its thiazolidine ring easily interconverts between endo and exo puckers due to a small energy barrier, which leads to destabilize polyproline helices. Collagen, composed of three polyproline II helices, mainly consists of X-Y-Gly triplets, where X is often proline and Y is frequently (2S,4R)hydroxyproline. In this study, we incorporated Thp into either position-X or position-Y to investigate the consequences of such a replacement on the triple helix. Circular dichroism and differential scanning calorimetry analyses showed that the Thp-containing collagen-mimetic peptides (CMPs) can fold into stable triple helices, in which the substitution at position-Y exhibits a larger destabilization effect. Additionally, we also prepared the derivative peptides by oxidizing Thp in the peptide to N-formyl-cysteine or S,S-dioxide Thp.

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“…In nature, three collagen single strands form a right‐handed triple helix that is stabilized through interstrand H‐bonds and intrastrand n→π* interactions between neighboring amides [15,23] . CMPs bearing γ‐aminoproline (Amp), Azp, or aminooxyproline (Aop) allowed for derivatization of collagen triple helices via amidation, copper(I)‐catalyzed azide alkyne cycloaddition (CuAAC), and oxime ligation, both in vitro and in vivo [21,24–29] . We envisioned that the isonitrile functional group would complement these extant technologies and allow for dual labelling.…”

Section: Introductionmentioning

confidence: 99%

Isonitrile‐Proline ‐ A Versatile Handle for the Chemoselective Derivatization of Collagen Peptides

Antoniazzi

Schäfer

Biedermann

et al. 2023

Chemistry A European J

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Functional groups that allow for chemoselective and bioorthogonal derivatization are valuable tools for the labelling of peptides and proteins. The isonitrile is such a group but synthetic methods for its incorporation into peptides by solid‐phase peptide synthesis are not known. Here, we introduce (4S)‐ and (4R)‐isonitrileproline (Inp) as building blocks for solid‐phase peptide synthesis. Conformational studies of (4S)‐ and (4R)‐Inp and thermal stability analysis of Inp‐containing collagen triple helices revealed that the isonitrile group exerts a stereoelectronic gauche effect. We showcase the value of Inp for bioorthogonal labelling by derivatization of Inp‐containing collagen model peptides (CMPs). Dual labelling with a pair of bioorthogonal reactions of a CMP containing Inp and azidoproline residues further highlights the versatility of the new isonitrile‐containing amino acids.

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γ‐Azaproline Confers pH Responsiveness and Functionalizability on Collagen Triple Helices

Cited by 8 publications

References 61 publications

Decoding Collagen Triple Helix Stability by Means of Hybrid DFT Simulations

Decoding Collagen Triple Helix Stability by Means of Hybrid DFT Simulations

Consequences of incorporating thiaproline and its oxidized derivatives into collagen triple helices

Isonitrile‐Proline ‐ A Versatile Handle for the Chemoselective Derivatization of Collagen Peptides

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