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4-Fluoroprolines: Conformational Analysis and Effects on the Stability and Folding of Peptides and Proteins

Part of the Topics in Heterocyclic Chemistry book series (TOPICS,volume 48)

Abstract

Proline is unique among proteinogenic amino acids because a pyrrolidine ring links its amino group to its side chain. This heterocycle constrains the conformations of the main chain and thus templates particular secondary structures. Proline residues undergo posttranslational modification at the 4-position to yield 4-hydroxyproline, which is especially prevalent in collagen. Interest in characterizing the effects of this modification led to the use of 4-fluoroprolines to enhance inductive properties relative to the hydroxyl group of 4-hydroxyproline and to eliminate contributions from hydrogen bonding. The strong inductive effect of the fluoro group has three main consequences: enforcing a particular pucker upon the pyrrolidine ring, biasing the conformation of the preceding peptide bond, and accelerating cistrans prolyl peptide bond isomerization. These subtle yet reliable modulations make 4-fluoroproline incorporation a complement to traditional genetic approaches for exploring structure–function relationships in peptides and proteins, as well as for endowing peptides and proteins with conformational stability.

Keywords

  • Collagen
  • Gauche effect
  • n → π* interaction
  • Pyrrolidine
  • Stereoelectronic effect

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Scheme 1
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Acknowledgments

This paper is dedicated to the memory of Grant R. Krow (1942–2015), our long-time collaborator on research on 4-fluoroprolines and their analogs. R.W.N. was supported by Biotechnology Training Grant T32 GM008349 (NIH), the Nelson J. Leonard Graduate Fellowship of the ACS Division of Organic Chemistry sponsored by Organic Syntheses, and an Eastman Summer Research Award from the Eastman Chemical Company. Work on 4-fluoroprolines in the Raines laboratory was supported by Grant R01 AR044276 (NIH).

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Newberry, R.W., Raines, R.T. (2016). 4-Fluoroprolines: Conformational Analysis and Effects on the Stability and Folding of Peptides and Proteins. In: Lubell, W. (eds) Peptidomimetics I. Topics in Heterocyclic Chemistry, vol 48. Springer, Cham. https://doi.org/10.1007/7081_2015_196

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