Exploring and Exploiting Polar−π Interactions with Fluorinated Aromatic Amino Acids

Abstract

Fluorination has become an increasingly attractive strategy in protein engineering for both basic research and biomedical applications. Thus researchers would like to understand the consequences of fluorination to the structure, stability, and function of target proteins. Although a substantial amount of work has focused on understanding the properties of fluorinated aliphatic amino acids, much less is known about fluorinated aromatic residues. In addition, polar-π interactions, often referred to as aromatic interactions, may play a significant role in protein folding and protein-protein interactions. Fluorination of aromatic residues presents an ideal strategy for probing polar-π interactions in proteins. This Account summarizes the recent studies of the incorporation of fluorinated aromatic amino acids into proteins. Herein we discuss the effects of fluorinating aromatic residues and rationalize them in the context of polar-π interactions. The results strongly support the proposal that polar-π interactions are energetically significant to protein folding and function. For example, an edge-face interaction of a pair of phenylalanines contributes as much as -1 kcal/mol to protein stability, while cation-π interactions can be much stronger. Furthermore, this new knowledge provides guidelines for protein engineering with fluorination. Importantly, incorporating perfluorinated aromatic residues into proteins enables novel mechanisms of molecular recognition that do not exist in native proteins, such as arene-perfluoroarene stacking. Such novel mechanisms can be used for programming protein folding specificity and engineering peptide-based materials.

Photocontrolled chignolin-derived β-hairpin peptidomimetics

“…Therefore, the peptide AzoChig1 (GYDP-AMPP-GTWG) was designed, in which the two central amino acids Glu5 and Thr6 of chignolin's four-residue turn sequence were substituted by AMPP (Fig. 20,21 However, systematic studies towards structure-guiding effects of fluorinated amino acids have mostly focused on a-helical systems 19,22 and only a limited number of approaches for fluorination of specific b-sheet positions have been reported, so far. Besides, peptidomimetic AzoChig2 (GYDP-AMPP-GT(5FW)G) with a 5-fluoro-Ltryptophan (5FTrp, 5FW) residue instead of Trp9 was synthesized to enhance key hydrophobic interactions between aromatic Tyr2 and Trp9.…”

Folding stability modulation of the villin headpiece helical subdomain by 4‐fluorophenylalanine and 4‐methylphenylalanine

“…The moderate stability even makes HP36 a good model protein used in the coating layer of nanoparticles for a laser‐induced thermal study . In previous studies, various forces and factors, including hydrogen bonding, aromatic–aromatic interactions, aromatic–proline interactions, hydrophobic interactions, cation–π interactions and steric effects, have been shown to affect the structure of HP36 . Recently, our study has also demonstrated that the proline puckering effect from various 4‐substituted proline derivatives can weaken the Pro…Trp interaction and induce hydrophobic effects as well, thereby affecting the stability of HP36 .…”

Adsorbate-Induced Modification of the Confining Barriers in a Quantum Box Array

“…Section 3.2 in Synthesis file) and typically in crystals of molecules with aryl and perfluoroaryl sub-units. [40][41][42][43][44] The on-surface 2D network is mainly comprised of regular pores enclosed by six Zn(II) porphyrin molecules 1 (Fig. 2, Fig.…”