Structure, folding, and energetics of cooperative interactions between the beta-strands of a de novo sesigned three-stranded antiparallel beta-sheet peptide

The effect of cooperative interactions between β-strands in enhancing β-sheet stability has been examined quantitatively by NMR using rationally designed synthetic peptides [β-hairpin (2β) and related 24-residue three-stranded antiparallel β-sheet (3β)] which are significantly folded in aqueous solution. The two hairpin components of 3β show quite different temperature-dependent stability profiles showing that a two-state model for folding (random coil ↔ three-stranded antiparallel β-sheet) is inappropriate. A four-state model for folding, involving intermediate C- and N-terminal β-hairpin conformations, is more consistent with the data. Thermodynamic analysis shows that folding of the C-terminal hairpin of 3β is entropy-driven, as previously described for the isolated hairpin 2β, but that the N-terminal hairpin, which is stabilized by a motif of aromatic residues (W4, F6, and Y11), is enthalpy-driven, consistent with stabilization through π−π interactions that are electrostatic in origin. NOE data, as we...