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Different QM/MM approaches to study enzymatic reactions: ppGalNAcT2 glycosyltransferase

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JANOŠ Pavel TRNKA Tomáš KOZMON Stanislav TVAROŠKA Igor KOČA Jaroslav

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Popis Glycosyltransferases are enzymes that catalyze the formation of glycosidic bonds. Polypeptide UDP-GalNAc transferase 2 (ppGalNAcT2) is a metal dependent retaining glycosyltransferase. It catalyzes the transfer of GalNAc moiety from UDP-GalNAc to the hydroxyl group of either threonine or serine residue on the target protein. We use the ppGalNAcT2 as a case study to compare different QM/MM methodologies that can provide reaction paths, transition state information and either free energy or potential energy of an enzymatic reaction. The methods used include QM/MM Ab Initio MD at the DFT level using CPMD coupled with either metadynamics (MTD) or String Method (STM). The STM is used to derive the minimum free energy reaction path. The geometrical features of the free energy path and the energy profile are compared with minimum potential energy path obtained at much lower computational cost using Nudged Elastic Band (NEB) method. The MTD provides the free energy surface of the reaction. This surface represents a rough overview of the reaction and can confirm the physical relevance of optimized paths or potentially provide an initial guess for path optimization methods. As a validation of the suitability of DFT for the study of glycosyltransferase enzymatic reactions, we compared several widely used functionals with high-level DLPNO-CCSD(T)/CBS data using the potential energy profile from NEB.