Tyrosine sulfation alters the biological activity of many proteins involved in different physiological and pathophysiological conditions, such as non-specific immune reaction, response to inflammation and ischemia, targeting of leukocytes and stem cells, or the formation of cancer metastases. Tyrosine sulfation is catalyzed by the enzymes tyrosylprotein sulfotransferases (TPST). In this study, we used QM/MM Car-Parrinello metadynamics simulations together with QM/MM potential energy calculations to investigate the catalytic mechanism of isoform TPST-1. The structural changes along the reaction coordinate are analyzed and discussed. Furthermore, both the methods supported the SN2 type of catalytic mechanism. The reaction barrier obtained from CPMD metadynamics was 12.8 kcal mol-1, and the potential energy scan led to reaction barriers of 11.6 kcal mol-1 and 13.7 kcal mol-1 with the B3LYP and OPBE functional, respectively. The comparison of the two methods (metadynamics and potential energy scan) may be helpful for future mechanistic studies. The insight into the reaction mechanism of TPST-1 might help with the rational design of transition-state TPST inhibitors.

Central European Institute of Technology Masaryk University Brno Czech Republic

Institute of Chemistry Slovak Academy of Sciences Bratislava Slovak Republic

National Center for Biomolecular Research Faculty of Science Masaryk University Brno Czech Republic

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