Evaluating β-turn mimics as β-sheet folding nucleators

Amelia A. Fuller, Deguo Du, Feng Liu, Jennifer E. Davoren, Gira Bhabha, Gerard Kroon, David A. Case, H. Jane Dyson, Evan T. Powers, Peter Wipf, Martin Gruebele, Jeffery W. Kelly

Research output: Contribution to journalArticlepeer-review


β-Turns are common conformations that enable proteins to adopt globular structures, and their formation is often rate limiting for folding. β-Turn mimics, molecules that replace the i + 1 and i + 2 amino acid residues of a β-turn, are envisioned to act as folding nucleators by preorganizing the pendant polypeptide chains, thereby lowering the activation barrier for β-sheet formation. However, the crucial kinetic experiments to demonstrate that β-turn mimics can act as strong nucleators in the context of a cooperatively folding protein have not been reported. We have incorporated 6 β-turn mimics simulating varied β-turn types in place of 2 residues in an engineered β-turn 1 or β-bulge turn 1 of the Pin 1WWdomain, a three-stranded β-sheet protein. We present 2 lines of kinetic evidence that the inclusion of β-turn mimics alters β-sheet folding rates, enabling us to classify β-turn mimics into 3 categories: those that are weak nucleators but permit Pin WW folding, native-like nucleators, and strong nucleators. Strong nucleators accelerate folding relative to WW domains incorporating all β-amino acid sequences. A solution NMR structure reveals that the native PinWW β-sheet structure is retained upon incorporating a strong E-olefin nucleator. These β-turn mimics can now be used to interrogate protein folding transition state structures and the 2 kinetic analyses presented can be used to assess the nucleation capacity of other β-turn mimics.

Original languageEnglish (US)
Pages (from-to)11067-11072
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
StatePublished - Jul 7 2009


  • Beta-sheet nucleator
  • Kinetic assessment of turn mimics
  • Pin WW domain
  • Protein folding

ASJC Scopus subject areas

  • General


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