4-Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix†

  1. Matthew D. Shoulders1,
  2. Ilia A. Guzei1,
  3. Ronald T. Raines1,2,*

Article first published online: 15 OCT 2007

DOI: 10.1002/bip.20864

Issue

Biopolymers

Biopolymers

Special Issue: This issue is dedicated to the memory of Elkan R. Blout, a founding editor of Biopolymers

Volume 89, Issue 5, pages 443–454, May 2008

Additional Information

How to Cite

Shoulders, M. D., Guzei, I. A. and Raines, R. T. (2008), 4-Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix. Biopolymers, 89: 443–454. doi: 10.1002/bip.20864

Author Information

  1. 1

    Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706-1322

  2. 2

    Department of Biochemistry, University of Wisconsin–Madison, 433 Babcock Drive, Madison, WI 53706-1544

*Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706-1322

  1. †

    This work is dedicated to the memory of Elkan R. Blout, a pioneer of spectroscopic methods for the structural characterization of proteins and peptides. Professor Blout was among the first to employ collagen-mimetic peptides for the study of native collagen structure, an approach that continues to provide important insights.

Publication History

  1. Issue published online: 28 FEB 2008
  2. Article first published online: 15 OCT 2007
  3. Manuscript Accepted: 5 OCT 2007
  4. Manuscript Revised: 2 OCT 2007
  5. Manuscript Received: 15 AUG 2007

Funded by

  • NIH. Grant Numbers: AR44276, RR13790, P41 RR02301
  • NSF. Grant Number: BIR-9512577

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Keywords:

  • 4-chloroproline;
  • collagen;
  • polyproline II-type helix;
  • proline;
  • prolyl peptide-bond isomerization;
  • triple helix

Abstract

Collagen is an abundant, triple-helical protein comprising three strands of the repeating sequence: Xaa–Yaa–Gly. (2S)-Proline and (2S,4R)-4-hydroxyproline (Hyp) are common in the primary structure of collagen. Here, we use nonnatural proline derivatives to reveal determinants of collagen stability. Specifically, we report high-yielding syntheses of (2S,4S)-4-chloroproline (clp) and (2S,4R)-4-chloroproline (Clp). We find that the molecular structure of Ac-Clp-OMe in the solid state is virtually identical to that of Ac-Hyp-OMe. In contrast, the conformational properties of Ac-clp-OMe are similar to those of Ac-Pro-OMe. Ac-Clp-OMe has a stronger preference for a trans amide bond than does Ac-Pro-OMe, whereas Ac-clp-OMe has a weaker preference. (Pro–Clp–Gly)10 forms triple helices that are significantly more stable than those of (Pro–Pro–Gly)10. Triple helices of (clp–Pro–Gly)10 have stability similar to those of (Pro–Pro–Gly)10. Unlike (Pro–Clp–Gly)10 and (clp–Pro–Gly)10, (clp–Clp–Gly)10 does not form a stable triple helix, presumably due to a deleterious steric interaction between proximal chlorines on different strands. These data, which are consistent with previous work on 4-fluoroprolines and 4-methylprolines, support the importance of stereoelectronic and steric effects in the stability of the collagen triple helix and provide another means to modulate that stability. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 443–454, 2008.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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