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Published online before print August 31, 2007, 10.1110/ps.073004907
Protein Science (2007), 16:2233-2239. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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The role of the turn in beta-hairpin formation during WW domain folding

Tim Sharpe1,3, Amanda L. Jonsson2,3, Trevor J. Rutherford1, Valerie Daggett2, and Alan R. Fersht1

1 MRC Centre for Protein Engineering and Cambridge University Chemical Laboratory, MRC Centre, Cambridge CB2 0QH, United Kingdom
2 Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195-7610, USA

(RECEIVED May 17, 2007; FINAL REVISION July 16, 2007; ACCEPTED July 17, 2007)

The folding of WW domains is rate limited by formation of a beta-hairpin comprising residues from strands 1 and 2. Residues in the turn of this hairpin have reported {Phi}-values for folding close to 1 and have been proposed to nucleate folding. High {Phi}-values do not necessarily imply that the energetics of formation are a driving force for initiating folding. We demonstrate by NMR studies and molecular dynamics simulations that the first turn of the hYAP, FBP28, and PIN1 WW domains is structurally dynamic and solvent exposed in the native and folding transition states. It is, therefore, unlikely that the formation of the beta-turn per se provides the energetic driving force for hairpin folding. It is more likely that the turn acts as an easily formed hinge that facilitates the formation of the hairpin; it is a nucleus as defined by the nucleation–condensation mechanism whereby a diffuse nucleus is stabilized by associated interactions.

Keywords: protein structure/folding; NMR spectroscopy; computational analysis of protein structure


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