Proceedings - Interdisciplinary Center for Nanotoxicity

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98 Conference on Current Trends in Computational Chemistry 2009 Mechanism of Enzymatic Phosphoryl Transfer Reactions: Associative vs. Dissociative Pathways Gábor Náray‐Szabó Laboratory of Structural Chemistry and Biology & HASELTE Protein Modelling Group, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary It is generally supposed that enzymatic phosphoryl transfer may follow two pathways (see Figure) [1]. In the dissociative mechanism (top) a trigonal metaphosphate intermediate is formed, while the associative mechanism (bottom) involves a relatively stable, trigonal bipyramidal intermediate, which refers to a local energy minimum on the reaction path [2,3]. However, a third option has to be mentioned, too, this is the classical SN2 mechanism with a trigonal bipyramidal transition state, referring to a maximum on the energy path [4]. The preferred pathway is determined by the nature of the phosphorus electrophile, the nucleophile, and the reaction medium (solvent or enzyme active site). Earlier computer simulations indicate that associative and dissociative mechanisms are similarly favored in the aqueous phase, and also calculations for different enzymes support either dissociative or associative pathways depending on a variety of factors. I will present some examples for all three types of reaction and stress the importance of the quantum mechanical approach in the appropriate interpretation of experimental data. References 1 Klähn, M., Rosta, E., and Warshel, A. (2006). J. Am. Chem. Soc. 128, 15310. 2 Lahiri, S.D., Zhang, G., Dunaway‐Mariano, D., and Allen, K.N. (2003). Science 299, 2067. 3 Barabás, O., Pongrácz, V., Kovári, J., Wilmanns, M., and Vértessy, B.G, (2004). J. Biol. Chem. 279, 42907. 4 Bernardi, F., Bottoni, A., De Vivo, M., Garavelli, M., Keserű, G.M., and Náray‐Szabó, G. (2002). Chem. Phys. Lett. 362, 1. 5 Berente, I., Beke, T., and Náray‐Szabó, G. (2007). Theor. Chem. Acc. 118, 129.
Conference on Current Trends in Computational Chemistry 2009 DFT study on formation of annelated 1,5‐benzodiazepine derivatives Sergiy I. Okovytyy, 1,2 Liudmyla K. Sviatenko, 2,3 Alexandr A. Gaponov, 1 Liliya I. Kasyan, 1 Igor Tarabara, 1 and Jerzy Leszczynski 2 1 Dnepropetrovsk National University, Dnepropetrovsk, 49050, Ukraine 2 Interdisciplinary Center for Nanotoxicity, Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217 USA 3 Kirovograd State Pedagogical University, Kirovograd, 25006, Ukraine In recent years, a great effort has been made in the benzodiazepine area to synthesize new tri‐ and tetraheterocyclic systems, which possess a wide range of biological activity. The mechanisms of formation of different annelated heterocycles using the 4‐methyl‐1,3‐dihydro‐ 1,5‐benzodiazepin‐2‐one as a starting material were investigated at the PCM/MP2/6‐ 311++G**//B3LYP/6‐311+G* level of theory. H N N N 2 O CH 3 N PhCCl=NNHPh 8 9 7 6 C 2 H 5 O 10 H N N N N 1 11 5 1 O CH 3 (C 2 H 5 O) 3 CH OC H 2 5 O CH 3 ClCH 2 CN NH 2 NH 2 The obtained results show that the direction of cyclization of 4‐methyl‐1,3‐dihydro‐1,5‐ benzodiazepin‐2‐one depends on the structure of an attacking reagent. The attachment of reagents to two atoms (N1 and O, N1 and C2, C4 and N5) of benzodiazepin‐2‐one results in formation of annelated heterocyclic systems. 4 2 3 4 N N N N 3 5 NH 2 N O CH 3 CH 3 99
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