Sequence dependence of β‐hairpin structure: Comparison of a salt bridge and an aromatic interaction

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Abstract
A comparison of the contributions and position dependence of cross‐strand electrostatic and aromatic side‐chain interactions to β‐sheet stability has been performed by using nuclear magnetic resonance in a well‐folded β‐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 α‐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.