Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, United States.
Department of Chemistry, Indian Institute of Science Education and Research Pune, Pashan, Pune 411008, India.
ACS Chem Biol. 2023 Dec 15;18(12):2555-2563. doi: 10.1021/acschembio.3c00553. Epub 2023 Nov 17.
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 (EF) geometry. Yet, the origins and the contribution of this EF 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 EF geometry was, in fact, stabilized by an intricate combination of XH/π interactions. By tuning the π-electron density of Trp rings, CH/π interactions are strengthened to gain additional stability. On the contrary, our DFT calculations support the notion that Trp modulations are challenging due to their simultaneous paradoxical engagement as H-bond donors in CH/π and acceptors in NH/π interactions.
色氨酸拉链（Trpzip）是β发夹肽的标志性折叠基序，利用两对跨链色氨酸，每对都通过边缘到面（EF）几何结构中的芳族-芳族堆积稳定。然而，这种 EF 堆积对独特的 Trpzip 稳定性的起源和贡献仍知之甚少。为了解决结构稳定性关系的问题，通过引入易于获得的具有不同电子密度的非蛋白质色氨酸，开发了 Trpzip 发夹文库。我们发现，实际上，每个 EF 几何结构都是通过复杂的 XH/π 相互作用组合稳定的。通过调整色氨酸环的π电子密度，可以增强 CH/π 相互作用以获得额外的稳定性。相反，我们的 DFT 计算支持这样一种观点，即由于 Trp 调节同时作为 CH/π 中的 H 键供体和 NH/π 中的受体参与，因此具有挑战性。
