Hydrogen bond surrogate helices as minimal mimics of protein α-helices

Ganesh S. Jedhe, Paramjit S. Arora

Research output: Chapter in Book/Report/Conference proceedingChapter


Examination of complexes of proteins with biomolecular ligands reveals that proteins tend to interact with partners via folded sub-domains, in which the backbone possesses secondary structure. α-Helices comprising the largest class of protein secondary structures, play fundamental roles in a multitude of highly specific protein-protein and protein-nucleic acid interactions. We have demonstrated a unique strategy for stabilization of the α-helical conformation that involves replacement of one of the main chain i and i + 4 hydrogen bonds in the target α-helix with a covalent bond. We termed this synthetic strategy a hydrogen bond surrogate (HBS) approach. Two salient features of this approach are: (1) the internal placement of the crosslink allows development of helices such that none of the solvent-exposed surfaces are blocked by the constraining element, i.e., all side chains of the constrained helices remain available for molecular recognition. (2) This approach can be deployed to constrain very short peptides (< 10 amino acid residues) into highly stable α-helices. This chapter presents the biophysical basis for the development of the hydrogen bond surrogate approach, as well as methods for the synthesis and conformational analysis of the artificial helices.

Original languageEnglish (US)
Title of host publicationSynthetic and Enzymatic Modifications of the Peptide Backbone
EditorsE. James Petersson
PublisherAcademic Press Inc.
Number of pages25
ISBN (Print)9780128212530
StatePublished - Jan 2021

Publication series

NameMethods in enzymology
PublisherAcademic Press Inc.
ISSN (Print)0076-6879


  • Mimics
  • Peptides
  • Peptidomimetics
  • Protein-protein interactions
  • Stabilized α-helices
  • Proteins
  • Protein Conformation, alpha-Helical
  • Hydrogen Bonding
  • Protein Structure, Secondary
  • Protein Conformation

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry


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