The precious fluorine on the ring: fluorine NMR for biological systems
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The precious fluorine on the ring: fluorine NMR for biological systems Andras Boeszoermenyi1,2 · Barbara Ogórek3 · Akshay Jain1 · Haribabu Arthanari1,2 · Gerhard Wagner2 Received: 17 April 2020 / Accepted: 29 June 2020 © Springer Nature B.V. 2020
Abstract The fluorine-19 nucleus was recognized early to harbor exceptional properties for NMR spectroscopy. With 100% natural abundance, a high gyromagnetic ratio (83% sensitivity compared to 1H), a chemical shift that is extremely sensitive to its surroundings and near total absence in biological systems, it was destined to become a favored NMR probe, decorating small and large molecules. However, after early excitement, where uptake of fluorinated aromatic amino acids was explored in a series of animal studies, 19F-NMR lost popularity, especially in large molecular weight systems, due to chemical shift anisotropy (CSA) induced line broadening at high magnetic fields. Recently, two orthogonal approaches, (i) C F3 labeling and (ii) aromatic 19F-13C labeling leveraging the TROSY (Transverse Relaxation Optimized Spectroscopy) effect have been successfully applied to study large biomolecular systems. In this perspective, we will discuss the fascinating early work with fluorinated aromatic amino acids, which reveals the enormous potential of these non-natural amino acids in biological NMR and the potential of 19F-NMR to characterize protein and nucleic acid structure, function and dynamics in the light of recent developments. Finally, we explore how fluorine NMR might be exploited to implement small molecule or fragment screens that resemble physiological conditions and discuss the opportunity to follow the fate of small molecules in living cells. Keywords Fluorine NMR · TROSY · Nucleic acids · Proteins · Drug discovery · 4-fluorophenylalanine
Introduction Due to an anisotropic distribution of electrons in the fluorine 2p orbitals, fluorine resonances are exquisitely sensitive to subtle differences in their van der Waals and electrostatic environments (Hennig et al. 2006; Ye et al. 2016). However, this anisotropic electron distribution also gives rise to chemical shift anisotropy (CSA). The contribution of CSA to transverse relaxation increases rapidly with the magnetic field and the molecular weight of the system under
* Andras Boeszoermenyi [email protected] * Gerhard Wagner [email protected] 1
Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
3
Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital and, Harvard Medical School, Boston, MA 02115, USA
investigation, limiting the applicability of fluorine NMR at high magnetic fields for biological systems. Two orthogonal approaches have been developed to address this problem. (i) Site-specific labeling of cysteine residues with C F3-car
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