Tunable CH/π Interactions within a Tryptophan Zipper Motif to Stabilize the Fold of Long β‑Hairpin Peptides

The
tryptophan zipper (Trpzip) is an iconic folding motif of β-hairpin
peptides capitalizing on two pairs of cross-strand tryptophans, each
stabilized by an aromatic–aromatic stacking in an edge-to-face
(EtF) geometry. Yet, the origins and the contribution
of this EtF packing to the unique Trpzip stability
remain poorly understood. To address this question of structure–stability
relationship, a library of Trpzip hairpins was developed by incorporating
readily accessible nonproteinogenic tryptophans of varying electron
densities. We found that each EtF geometry was, in
fact, stabilized by an intricate combination of XH/π interactions.
By tuning the π-electron density of Trpface rings, CH/π interactions are strengthened to gain additional
stability. On the contrary, our DFT calculations support the notion
that Trpedge modulations are challenging
due to their simultaneous paradoxical engagement as H-bond donors
in CH/π and acceptors in NH/π interactions.