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 (E t F) geometry. Yet, the origins and the contribution of this E t F 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 E t F geometry was, in fact, stabilized by an intricate combination of XH/π interactions. By tuning the π-electron density of Trp face rings, CH/π interactions are strengthened to gain additional stability. On the contrary, our DFT calculations support the notion that Trp edge modulations are challenging due to their simultaneous paradoxical engagement as H-bond donors in CH/π and acceptors in NH/π interactions.