Skip to content

Engineering protein stability with atomic precision in a monomeric miniprotein

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)764-770
Number of pages7
JournalNature Chemical Biology
Issue number7
Early online date22 May 2017
DateAccepted/In press - 4 Jan 2017
DateE-pub ahead of print - 22 May 2017
DatePublished (current) - 1 Jul 2017


Miniproteins simplify the protein-folding problem, allowing the dissection of forces that stabilize protein structures. Here we describe PPα-Tyr, a designed peptide comprising an α helix buttressed by a polyproline-II helix. PPα-Tyr is water soluble, monomeric, and unfolds cooperatively with a midpoint unfolding temperature (TM) of 39 ˚C. NMR structures of PPα-Tyr reveal proline residues docked between tyrosine side chains as designed. The stability of PPα is sensitive to the aromatic residue: replacing tyrosine by phenylalanine, i.e. changing three solvent-exposed hydroxyl groups to protons, reduces the TM to 20 ˚C. We attribute this to the loss of CH–π interactions between the aromatic and proline rings, which we probe by substituting the aromatic residues with non-proteinogenic side chains. In analyses of natural protein structures we find a preference for proline-tyrosine interactions over other proline-containing pairs, and abundant CH–π interactions in biologically important complexes between proline-rich ligands and SH3 and similar domains.

    Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Download statistics

No data available



  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Nature at Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 1 MB, PDF document


View research connections

Related faculties, schools or groups