Capturing dynamically interacting inhibitor by paramagnetic NMR spectroscopy

Pavel Srb,¹ Michal Svoboda,¹ Ladislav Benda,² Martin Lepšík,¹ Ján Tarábek, ¹ Václav Šícha,³ Bohumír Grüner,³ Klára Grantz-Šašková,¹ Jiří Brynda,^1,4 Pavlína Řezáčová,^1,4 Jan Konvalinka,¹ and Václav Veverka^1*

¹Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic

²Institute des Sciences Analytiques, UMR 5280 CNRS / Université Claude Bernard Lyon 1 / ENS de Lyon, 5 rue de la Doua, 69100 Villeurbanne (Lyon), France

³Institute of Inorganic Chemistry of the Czech Academy of Sciences, Husinec-Řež u Prahy, Czech Republic

⁴Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic

Transient and fuzzy intermolecular interactions are fundamental to many biological processes. Despite their importance, they are notoriously uneasy to characterize. Paramagnetic NMR provides an opportunity to amplify rather small indices of intermolecular interactions often observed with diamagnetic ligands. Here, we present an intricate case of a partially flexible protein dynamically interacting with a ligand where data obtained by standard approaches fail to provide detailed structural interpretation. We demonstrate, that a combination of paramagnetic NMR experiments, advanced quantum chemical calculations and molecular dynamics simulations offer a route towards structural characterization of a class of inhibitors based on substituted metalacarboranes with HIV-1 protease.