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The result of the action of C2GnT is the core 2 structure that is essential for the further elongation of the carbohydrate chains of <jats:italic>O<\/jats:italic>\u2010glycans. The catalytic mechanism of this metal\u2010ion\u2010independent glycosyltransferase is of paramount importance and is investigated here by using quantum mechanical (QM) (density functional theory (DFT))\/molecular modeling (MM) methods with different levels of theory. The structural model of the reaction site used in this report is based on the crystal structures of C2GnT. The entire enzyme\u2013substrate system was subdivided into two different subsystems: the QM subsystem containing 206 atoms and the MM region containing 5914 atoms. Three predefined reaction coordinates were employed to investigate the catalytic mechanism. The calculated potential energy surfaces discovered the existence of a concerted S<jats:sub>N<\/jats:sub>2\u2010like mechanism. In this mechanism, a nucleophilic attack by O6 facilitated by proton transfer to the catalytic base and the separation of the leaving group all occur almost simultaneously. The transition state for the proposed reaction mechanism at the M06\u20102X\/6\u201031G** (with diffuse functions on the O1\u2032, O5\u2032, O<jats:sub>Glu<\/jats:sub>, and O6 atoms) level was located at C1\uf8ffO6=1.74\u2005\u00c5 and C1\uf8ffO1=2.86\u2005\u00c5. The activation energy for this mechanism was estimated to be between 20 and 29\u2005kcal\u2009mol<jats:sup>\u22121<\/jats:sup>, depending on the method used. These calculations also identified a low\u2010barrier hydrogen bond between the nucleophile O6H and the catalytic base Glu320, and a hydrogen bond between the <jats:italic>N<\/jats:italic>\u2010acetamino group and the glycosidic oxygen of the donor in the TS. It is proposed that these interactions contribute to a stabilization of TS and participate in the catalytic mechanism.<\/jats:p>","DOI":"10.1002\/chem.201300383","type":"journal-article","created":{"date-parts":[[2013,4,24]],"date-time":"2013-04-24T07:56:52Z","timestamp":1366790212000},"page":"8153-8162","source":"Crossref","is-referenced-by-count":19,"title":["A QM\/MM Investigation of the Catalytic Mechanism of Metal\u2010Ion\u2010Independent Core 2 \u03b21,6\u2010<i>N<\/i>\u2010Acetylglucosaminyltransferase"],"prefix":"10.1002","volume":"19","author":[{"given":"Igor","family":"Tvaro\u0161ka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislav","family":"Kozmon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela","family":"Wimmerov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaroslav","family":"Ko\u010da","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,4,24]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.08.022"},{"key":"e_1_2_6_2_2","unstructured":"\u00a0"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-4165(02)00409-9"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-065X.2002.18603.x"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.117.4.895"},{"key":"e_1_2_6_6_2","unstructured":"\u00a0"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1006\/smim.2001.0344"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1999.79.1.181"},{"key":"e_1_2_6_9_2","unstructured":"\u00a0"},{"key":"e_1_2_6_10_2","first-page":"263","volume-title":"Glycoconjugates. 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