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

Abstract

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 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.

De Novo Synthesis and Structural Elucidation of CDR-H3 Loop Mimics

“…In addition, the sheer broadness of the A4(H β ) resonance (restricted conformational ensemble in slow equilibrium on the NMR time scale) and its significant CSD of ̃ −0.84 ppm are evidence of a profound shielding interaction (Figure B,C). This would be consistent with a close contact CH/π interaction between A4 and W17 that is otherwise supported by several strong long-range NOESY correlations between W17(H ζ3/η2 ) and A4(H β ). − The large CSD of A4(H β ) was further observed across the entire series of bulge-like hairpins (Figure C). While all alanine-derived motifs presented a similar chemical shift deviation of the A4H β signals (−0.74 to −0.88 ppm), the valine of 1h endured a greater shielding effect of 1.02 ppm in addition to the H γ CSDs of −0.56 and −0.95 ppm.…”