The Polar Hydrophobicity of Fluorinated Compounds

Biffinger, Justin C.; Kim, Hong Woo; DiMagno, Stephen G.

doi:10.1002/chin.200429293

Cited by 36 publications

(68 citation statements)

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“…We thus conclude that the A6 and B7 affinity modulation with the fluorinated peptides is due largely to the unique “polar hydrophobicity” of fluorine [11]. Accordingly, with the A6 TCR, burial of the fluorinated side chain in the Tyr5 pocket results in a favorable electrostatic interaction with Arg95β, offsetting the arginine’s desolvation penalty.…”

Section: Resultsmentioning

confidence: 96%

“…Fluorine is hydrophobic and highly electronegative, yet it only rarely participates as a hydrogen bond acceptor due to its low polarizability [19-21]. Instead, fluorine interacts with full or partial positive charges via dipolar interactions, although the strength of these are subject to some debate [11]. A recent survey of complexes between proteins and fluorinated ligands in the Protein Data Bank highlighted the propensity for fluorine to interact with the guanidinium group of arginine [6].…”

Section: Resultsmentioning

confidence: 99%

“…As recently reviewed [6], due to fluorine’s unusual chemistry and a lack of detailed studies with fluorinated compounds, fluorine’s effects on the affinity of biomolecular interactions is poorly understood. Our structural and thermodynamic results indicated a unique “polar hydrophobicity” mechanism [11], as neither electrostatics nor hydrophobicity alone could explain the results.…”

Section: Introductionmentioning

confidence: 99%

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Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner

Piepenbrink

Borbulevych

Sommese

et al. 2009

Biochemical Journal

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Synopsis T cell receptor (TCR) recognition of antigenic peptides bound and presented by major histocompatibility complex (MHC) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide/MHC molecules weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Further, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. Here, we studied how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the HTLV-1 Tax11-19 peptide (Tax) enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with A6, independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, in probing the mechanism of fluorine’s effect on TCR binding, our data were most consistent with fluorine’s unique “polar hydrophobicity,” a finding which should impact other attempts to alter molecular recognition with fluorine.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner

Piepenbrink

Borbulevych

Sommese

et al. 2009

Biochemical Journal

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“…These properties may in some cases strengthen (or weaken) other types of noncovalent interactions with nearby atoms –examples include an effect on molecular packing and van der Waals interactions(43), hydrophobicity(44, 45), or dipole interactions(46, 47). For instance, the C-F bond of 2-FH253 is in a hydrophobic patch that is surrounded by Y219, L255 and I529.…”

Section: Resultsmentioning

confidence: 99%

Evidence That Histidine Protonation of Receptor-Bound Anthrax Protective Antigen Is a Trigger for Pore Formation

et al. 2010

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The protective antigen (PA) component of the anthrax toxin forms pores within the low pH environment of host endosomes, through mechanisms that are poorly understood. It has been proposed that pore formation is dependent on histidine protonation. In previous work, we biosynthetically incorporated 2-fluorohistidine (2-FHis), an isosteric analog of histidine with a significantly reduced pKa (~1), into PA, and showed that the pH-dependent conversion from the soluble prepore to a pore was unchanged. However, we also observed that 2-FHisPA was nonfunctional in the ability to mediate cytotoxicity of CHO-K1 cells by LF N -DTA, and was defective in translocation through planar lipid bilayers. Here, we show that the defect in cytotoxicity is due to both a defect in translocation and, when bound to the host cellular receptor, an inability to undergo low pH-induced pore formation. Combining X-ray crystallography with hydrogendeuterium (H-D) exchange mass spectrometry, our studies lead to a model in which hydrogen bonds to the histidine ring are strengthened by receptor binding. The combination of both fluorination and receptor binding is sufficient to block low pH-induced pore formation.Anthrax toxin is an AB toxin secreted by Bacillus anthracis and is required for disease pathogenesis (1). The B component, the protective antigen (PA), is an 83 kDa, four domain protein that binds to the extracellular von Willebrand factor A (vWA) integrin-like I domain 1 To whom correspondence should be addressed: Tel: (316) Fax: (316) 978-3431; Jim.Bann@wichita.edu. 2 Current address: Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas 79968-0519, USA 3 Current address: Department of Chemistry, University of Missouri-Columbia, 125 Chemistry Building, 601 S. College Avenue, Columbia, MO 65211-7600. Supporting informationSupplementary figures of translocation of LFN-DTA, a simulated-annealing omit map for the β1-β2 and β3-β4 loops, a figure showing the crystal contact between R344 and E224 and mass spectra of peptides used in the H-D exchange experiments. This material is free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2011 August 24. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of either one of two identified host cell receptors, anthrax toxin receptor 1/tumor endothelial marker 8 (ANTXR1/TEM8) or anthrax toxin receptor 2/capillary morphogenesis protein 2 (ANTXR2/CMG2) (2,3). Binding of PA to the receptor vWA domain is followed by cleavage of PA into two fragments of 63 kDa and 20 kDa, by a cell-surface furin protease (4), leading to the spontaneous formation of a ring-shaped heptameric (PA 63 ) 7 structure termed the prepore (5). Formation of the prepore creates binding sites for the enzymatic A components, edema factor (EF) and lethal factor (LF), which bind with a stoichiometry of three EF or LF's per prepore (6). In addition, PA has been shown recently to form functional octa...

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“…The strength of C-F bonds (O'Hagan, 2008), and their ability to impose unique conformational constraints (Gorres et al, 2008; Nieschalk et al, 1996) are important elements that support such designs. Moreover, the addition of multiple C-F bonds can increase stability to chemical oxidation (DiMagno et al, 1996) and metabolism, and provide additional driving force to enhance binding with macromolecular targets, in aqueous solution (Biffinger et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal Transduction

Panigrahi

Eggen

Maeng

et al. 2009

Chemistry & Biology

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SUMMARY This overview focuses on the (α,α-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction – pathways of great interest to drug development. The most versatile modes of access to these chemical biological tools are discussed, organized by method of PCF2-C bond. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a “constitutive phosphorylation” phenotype, and is seen to support native protein-protein interactions that depend upon serine phosphorylation. Signal transduction pathways studied with this chemical biological approach include the regulation of p53 tumor suppressor protein activity, and of melatonin production. Given these successes, the future is bright for the use of such “teflon phospho-amino acid mimics” to map kinase-based signaling pathways.

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The Polar Hydrophobicity of Fluorinated Compounds

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 36 publications

References 1 publication

Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner

Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner

Evidence That Histidine Protonation of Receptor-Bound Anthrax Protective Antigen Is a Trigger for Pore Formation

The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal Transduction

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