Next-Generation Tags for Fluorine Nuclear Magnetic Resonance: Designing Amplification of Chemical Shift Sensitivity.

Autor: Frere GA; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Hasabnis A; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Francisco CB; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada.; Department of Chemistry, State University of Maringá, 5790, Maringá 87020-900, Brazil., Suleiman M; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Alimowska O; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Rahmatullah R; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Gould J; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Su CY; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Voznyy O; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Gunning PT; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada., Basso EA; Department of Chemistry, State University of Maringá, 5790, Maringá 87020-900, Brazil., Prosser RS; Department of Chemistry, University of Toronto, CPS, UTM, 3359 Mississauga Rd, Mississauga, ON L5L 1C6, Canada.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2024 Feb 07; Vol. 146 (5), pp. 3052-3064. Date of Electronic Publication: 2024 Jan 27.
DOI: 10.1021/jacs.3c09730
Abstrakt: Fluorine NMR is a highly sensitive technique for delineating the conformational states of biomolecules and has shown great utility in drug screening and in understanding protein function. Current fluorinated protein tags leverage the intrinsic chemical shift sensitivity of the 19 F nucleus to detect subtle changes in protein conformation and topology. This chemical shift sensitivity can be amplified by embedding the fluorine or trifluoromethyl reporter within a pyridone. Due to their polarizability and rapid tautomerization, pyridones exhibit a greater range of electron delocalization and correspondingly greater 19 F NMR chemical shift dispersion. To assess the chemical shift sensitivity of these tautomeric probes to the local environment, 19 F NMR spectra of all possible monofluorinated and trifluoromethyl-tagged versions of 2-pyridone were recorded in methanol/water mixtures ranging from 100% methanol to 100% water. 4-Fluoro-2-pyridone and 6-(trifluoromethyl)-2-pyridone (6-TFP) displayed the greatest sensitivity of the monofluorinated and trifluoromethylated pyridones, exceeding that of known conventional CF 3 reporters. To evaluate the utility of tautomeric pyridone tags for 19 F NMR of biomolecules, the alpha subunit of the stimulatory G protein (G s α) and human serum albumin (HSA) were each labeled with a thiol-reactive derivative of 6-TFP and the spectra were recorded as a function of various adjuvants and drugs. The tautomeric tag outperformed the conventional tag, 2-bromo- N -(4-(trifluoromethyl)phenyl)acetamide through the improved resolution of several functional states.
Databáze: MEDLINE
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