| Institution: | 1. Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, 81377 Munich, Germany;2. Dept. Chemistry, Section Biochemistry, Johannes Gutenberg-Universität Mainz, 55128 Mainz, Germany
Centre for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany;3. Institute for Physical and Theoretical Chemistry, University of Würzburg, Emil-Fischer-Straße 42, 97074 Würzburg, Germany;4. Dept. Chemistry, Section Organic Chemistry, Johannes Gutenberg-Universität Mainz, 55128 Mainz, Germany;5. Institute of Structural Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany;6. Dept. Chemistry, Section Biochemistry, Johannes Gutenberg-Universität Mainz, 55128 Mainz, Germany |
| 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. |
