# Investigating the Site‐Specific Impact of Fluorine Substitution on Aromatic Interactions in a Tryptophan Zipper Peptide

## TL;DR

This study explores how adding fluorine to specific positions in a tryptophan zipper peptide affects its stability and aromatic interactions.

## Contribution

The paper introduces a systematic analysis of fluorine substitution effects on aromatic interactions in a tryptophan zipper peptide.

## Key findings

- Fluorine substitution alters the electron density and affects the stability of the Trpzip2 peptide.
- Site-specific fluorine incorporation reveals the importance of CH/π and NH/π interactions in Trp/Trp packing.
- The study shows that fluorine can be used to optimize aromatic interactions in peptides.

## 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.

Constitutional isomers of fluoro‐tryptophan alter the stability of the β‐hairpin peptide Trpzip2 by tuning key CH/π and NH/π interactions.