title: The role of the turn in beta-hairpin formation during WW domain folding.
abstract: 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.
authors.affiliation: MRC Centre for Protein Engineering and Cambridge University Chemical Laboratory, MRC Centre, Cambridge, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Sharpe
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Jonsson
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Valerie
authors.initials: V
authors.lastname: Daggett
authors.forename: Alan R
authors.initials: AR
authors.lastname: Fersht
mesh_terms: D006860:Hydrogen Bonding; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary