Sequence dependence of beta-hairpin structure: comparison of a salt bridge and an aromatic interaction.

A comparison of the contributions and position dependence of cross-strand electrostatic and aromatic side-chain interactions to beta-sheet stability has been performed by using nuclear magnetic resonance in a well-folded beta-hairpin peptide of the general sequence XRTVXVdPGOXITQX. Phe-Phe and Glu-Lys pairs were varied at the internal and terminal non-hydrogen-bonded position, and the resulting stability was measured by the effects on alpha-hydrogen and aromatic hydrogen chemical shifts. It was determined that the introduction of a Phe-Phe pair resulted in a more folded peptide, regardless of position, and a more tightly folded core. Substitution of the Glu-Lys pair at the internal position results in a less folded peptide and increased fraying at the terminal residues. Upfield shifting of the aromatic hydrogens provided evidence for an edge-face aromatic interaction, regardless of position of the Phe-Phe pair. In peptides with two Phe-Phe pairs, substitution with Glu-Lys at either position resulted in a weakening of the aromatic interaction and a subsequent decrease in peptide stability. Thermal denaturation of the peptides containing Phe-Phe indicates that the aromatic interaction is enthalpically favored, whereas the folding of hairpins with cross-strand Glu-Lys pairs was less enthalpically favorable but entropically more favorable.