When planning a fluorine labeling strategy for 19F solid state NMR (ssNMR) studies of the structure and/or mobility of fluorine labeled compounds in situ in an oriented biological system, it is important to characterize the NMR properties of the label. This manuscript focuses on the characterization of a selection of aromatic fluorine compounds in dimyristoylphosphatidylcholine bilayers using 19F ssNMR from the standpoint of determining the optimum arrangement of fluorine nuclei on a pendant aromatic ring before incorporation into more complex biological systems.
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Altenberger J, Gustafsson F, Harjola VP et al (2018) Levosimendan in acute and advanced heart failure: an appraisal of the clinical database and evaluation of its therapeutic applications. J Cardiovasc Pharmacol 71:129–136. https://doi.org/10.1097/FJC.0000000000000533
Arntson KE, Pomerantz WCK (2016) Protein-observed fluorine NMR: a bioorthogonal approach for small molecule discovery. J Med Chem 59:5158–5171. https://doi.org/10.1021/acs.jmedchem.5b01447
Ashbrook SE, Griffin JM, Johnston KE (2018) Annual review of analytical chemistry recent advances in solid-state nuclear magnetic resonance spectroscopy. Annu Rev Anal Chem 11:485–508. https://doi.org/10.1146/annurev-anchem
Boeszoermenyi A, Chhabra S, Dubey A et al (2019) Aromatic 19 F- 13 C TROSY: a background-free approach to probe biomolecular structure, function, and dynamics. Nat Methods 16:333–340. https://doi.org/10.1038/s41592-019-0334-x
Cory DG, Ritchey WM (1988) Suppression of signals from the probe in bloch decay spectra. J Magn Reson 80:128–132. https://doi.org/10.1016/0022-2364(88)90064-9
Dalvit C, Vulpetti A (2019) Ligand-based fluorine NMR screening: principles and applications in drug discovery projects. J Med Chem 62:2218–2244
Frisch MJ, Trucks GW, Schlegel HB et al (2004) Gaussian 03. Gaussian Inc., Wallingford CT
Grage SL, Ulrich AS (1999) Structural parameters from 19F homonuclear dipolar couplings, obtained by multipulse solid-state NMR on static and oriented systems. J Magn Reson 138:98–106. https://doi.org/10.1006/jmre.1999.1726
Griffin RG, Ellett JD, Mehring M et al (1972) Single crystal study of the 19 F shielding tensors of a trifluoromethyl group. J Chem Phys 57:2147–2155. https://doi.org/10.1063/1.1678543
Guo MP, Deng JH, Zhang QC et al (2008) 1-(2′,4′-Difluorobiphenyl-4-yl)ethanone. Acta Crystallogr Sect E. https://doi.org/10.1107/S1600536808028596
Hull WE, Sykes BD (1974) Fluorotyrosine alkaline phosphatase. 19F nuclear magnetic resonance relaxation times and molecular motion of the individual fluorotyrosines. Biochemistry 13:3431–3437
Hwang PM, Sykes BD (2015) Targeting the sarcomere to correct muscle function. Nat Rev Drug Discov 14:313–328. https://doi.org/10.1038/nrd4554
Kalbitzer HR, Rohr G, Nowak E et al (1992) A new high sensitivity19F probe for labeling cysteine groups of proteins. NMR Biomed 5:347–350. https://doi.org/10.1002/nbm.1940050605
Klein BA, Reiz B, Robertson IM et al (2018) Reversible covalent reaction of levosimendan with cardiac troponin C in vitro and in situ. Biochemistry 57:2256–2265. https://doi.org/10.1021/acs.biochem.8b00109
Klein BA, Robertson IM, Reiz B et al (2019) Thioimidate bond formation between cardiac troponin C and nitrile-containing compounds. ACS Med Chem Lett 10:1007–1012. https://doi.org/10.1021/acsmedchemlett.9b00168
Knowles AC, Irving M, Sun YB (2012) Conformation of the troponin core complex in the thin filaments of skeletal muscle during relaxation and active contraction. J Mol Biol 421:125–137. https://doi.org/10.1016/j.jmb.2012.05.005
Matsumori N, Kasai Y, Oishi T et al (2008) Orientation of fluorinated cholesterol in lipid bilayers analyzed by 19F tensor calculation and solid-state NMR. J Am Chem Soc 130:4757–4766. https://doi.org/10.1021/ja077580l
McDowell LM, McCarrick MA, Studelska DR et al (2003) Human factor Xa bound amidine inhibitor conformation by double rotational-echo double resonance nuclear magnetic resonance and molecular dynamics simulations. J Med Chem 46:359–363. https://doi.org/10.1021/jm0202324
Mehring M, Griffin RG, Waugh JS (1971) 19F shielding tensors from coherently narrowed NMR powder spectra. J Chem Phys 55:746–755. https://doi.org/10.1063/1.1676141
Müller K, Faeh C, Diederich F (2007) Fluorine in pharmaceuticals: looking beyond intuition. Science 80- 317:1881–1886. https://doi.org/10.1126/science.1131943
Pellecchia M, Sem DS, Wüthrich K (2002) NMR in drug discovery. Nat Rev Drug Discov 1:211–219. https://doi.org/10.1038/nrd748
Pineda-Sanabria SE, Robertson IM, Sun Y-B et al (2016) Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog. J Mol Cell Cardiol 92:174–184. https://doi.org/10.1016/j.yjmcc.2016.02.003
Robertson IM, Sun YB, Li MX, Sykes BD (2010) A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex. J Mol Cell Cardiol 49:1031–1041. https://doi.org/10.1016/j.yjmcc.2010.08.019
Robertson IM, Pineda-Sanabria SE, Yan Z et al (2016) Reversible covalent binding to cardiac troponin C by the Ca2+ -sensitizer levosimendan. Biochemistry 55:6032–6045. https://doi.org/10.1021/acs.biochem.6b00758
Sanders LK, Oldfield E (2001) Theoretical investigation of 19F NMR chemical shielding tensors in fluorobenzenes. J Phys Chem A 105:8098–8104. https://doi.org/10.1021/jp011114f
Singh J, Petter RC, Baillie TA, Whitty A (2011) The resurgence of covalent drugs. Nat Rev Drug Discov 10:307–317. https://doi.org/10.1038/nrd3410
Sugiki T, Furuita K, Fujiwara T, Kojima C (2018) Current NMR techniques for structure-based drug discovery. Molecules 23:148. https://doi.org/10.3390/molecules23010148
The authors thank Kieran Cockburn for assistance in preparation of the DMPC samples with 4-FBA and 3,5-FBA.
This study was supported by grants from the Heart and Stroke Foundation of Canada (B.D.S., G-14-0005884), the Canadian Institutes of Health Research (CIHR) (B.D.S., 37769), the Faculty of Medicine Transitional Program and CIHR Fellowship (I.M.R, RES0020860).
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Robertson, I.M., Klein, B.A. & Sykes, B.D. Optimizing fluorine labelling for 19F solid-state NMR in oriented biological systems. J Biomol NMR 74, 1–7 (2020). https://doi.org/10.1007/s10858-019-00296-8
- 19F NMR
- Fluorine labelling
- Solid-state NMR
- Chemical shift anisotropy