Investigating the Site‐Specific Impact of Fluorine Substitution on Aromatic Interactions in a Tryptophan Zipper Peptide
Year: 2025
Type: article
Abstract: The stability of pairwise tryptophan (Trp) edge-to-face aromatic interactions has been exploited in the design of small tryptophan zipper (Trpzip) peptides. Herein, we report a systematic study of the regiospecific impact of four constitutional isomers of non-natural fluoro-Trp, regarding their incorporation at either edge- or face-positions. Single fluorine substituents affect the electron density of the indole moiety and introduce a highly electronegative component while the native geometry of Trp is maintained. We employed a library approach based on the sequence of Trpzip2 and assessed peptide structure and stability using CD, FTIR, and NMR spectroscopy. Global hairpin stability was improved or compromised upon site-specific incorporation of a single monofluoro-Trp regioisomer. Fluorine substitution revealed key CH/π interactions within the Trp/Trp packing and holds potential for the future optimization of aromatic interactions involving Trp.
Source: Chemistry - A European Journal
Authors: David Reiter, Ferhat Mutlu, Dominik Ebert, Marceline Noutio, Joachim Heberle, Mario Schubert, Beate Koksch
Institution: Freie Universität Berlin
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,640
OpenAlex ID: W4411451967