Stacked Fluoroaromatics as Supramolecular Synthons for Programming Protein Dimerization Specificity

Abstract

Aromatic “bonding”: Although known to exist in proteins, aromatic stacking interactions and the energetic factors important for it are not well understood. A systematic investigation of aromatic stacking interactions in a protein model system using a series of fluorinated phenylalanine analogues illustrates the importance of dipole–dipole and dipole–induced‐dipole coupling to the stability and self‐sorting properties of aromatic stacking pairs.

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

“…43 Our experiments show that, despite the size increase, fluorination of the core Phe residues is well accommodated by the R 2 D fold. In fact, fluorination of all core Phe residues dramatically improved the R 2 D structural stability (by ∼ À6 kcal/mol), with the melting temperatures increasing from 29°C for (F, F) to 80°C for (Z, Z).…”

“…The tetrafluorophenylalanines were obtained in high yields and enantiopurity through a facile four-step synthesis using the Seebach or Sch € ollkopf chiral auxiliary. 32,43 Our results show that F10Z o is more stable than F10Z by À1.1 kcal/mol, presumably because the F10ÀF6 edgeÀface interaction is retained by the F10Z o ( Figure 2C) mutant but not by F10Z. Similarly, by retaining the F6ÀF17 edgeÀface interaction, F6Z p affords an improved stability in comparison to F6Z, albeit by a smaller margin (À0.3 kcal/mol).…”

“…Furthermore, by capitalizing on both quadrupole stacking (FÀZ) and dipoleÀdipole interactions (F 345 FÀF 345 F), we demonstrate that self-sorting behavior can be afforded by stacked aromatic pairs (Figure 4). 43 Specifically, equilibration of a mixture of (F, F), (Z, Z) and (F 345 F, F 345 F) gives primarily two dimeric species: the heterodimer (F, F)À(Z, Z) and the homodimer of (F 345 F, F 345 F). These two dimers emerge exclusively out of six possible dimers presumably due to the synergy of the two favorable stacking pairs (FÀZ and F 345 FÀF 345 F).…”

Current Understanding of π–π Interactions and the Applications in Protein Design

“…By using α2D as a tractable system, Gao and coworkers investigated the energetics of π-π stacking and their role in stabilizing protein structures [12,13]. Researchers incorpo rated various fluorinated phenylalanine analogues into posi tions 10 and/or 29 of the α2D sequence.…”

Genetically encoded fluorophenylalanines enable insights into the recognition of lysine trimethylation by an epigenetic reader

“…We next tested the ability of PylRS-AS for the acceptance of other fluorophenylalanines including 2,3,4,5-tetrafluorophenylalaine (F 4 F), 14 3,4,5-trifluorophenylalanine (F 3 F), 3,5-difluorophenylalanine (F 2 F), and 3,4-difluorophenylalanine (F 2 F’). When these fluorophenylalanines were present in the growth medium, E. coli BL21 cells coding for PylRS-AS, tRNA Pyl and sfGFP2TAG expressed full-length sfGFP (Figure 2B).…”