Predicting ¹⁹F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex

Abstract

The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable 19F chemical‐shift predictions to deduce ligand‐binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the 19F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein–inhibitor conformations as well as monomeric and dimeric inhibitor–protein complexes, thus rendering it the largest computational study on chemical shifts of 19F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.

NMR parameters of FNNF as a test for coupled-cluster methods: CCSDT shielding and CC3 spin–spin coupling

“…As such, there is current interest in performing quantum mechanical calculations of shielding and spin-spin coupling constants for molecules that are difficult to investigate experimentally in order to validate and supplement experimental data. 4 Of particular interest is the accurate prediction of 19 F NMR data. Although many computational studies have been presented recently, [5][6][7][8][9][10][11][12][13][14][15][16] the determination of molecular magnetic properties of fluorine-containing molecules is still challenging for theoretical methods.…”

A Genetically Encoded F-19 NMR Probe Reveals the Allosteric Modulation Mechanism of Cannabinoid Receptor 1

“…Previous research has established that, upon ligand binding, GPCRs undergo conformational population changes among distinct states, which dictate their signaling profile. − While X-ray crystallography and cryo-EM methods usually capture the lowest-energy conformational state of proteins, NMR is uniquely capable of measuring multiple conformational populations of proteins in near-physiological conditions ,,− These studies relied mostly on post-translational cysteine-mediated chemical conjugation ,,− ,,, (Figure B and Figure S1). Nearly two-thirds of human GPCRs harbor more than 10 cysteine residues (Figure S2), and mutation of all surface-exposed cysteine residues may cause significant structural perturbation (Figure S3).…”

Extreme NMR shielding in fluoro-nitrogen cations

“…26–28 As such, there is current interest in performing shielding calculations for molecules such as N–F containing cations that are difficult to investigate experimentally. 29…”