QM/MM Study on the Structure and Reactivity of Oxygenation Enzymes Kazunari Yoshizawa Institute for Materials Chemistry and Engineering, Kyushu University Fukuoka 819-0395, Japan. Iron- and copper-based enzymes play an essential role in oxygenation reactions using dioxygen. My group has investigated structure-reactivity relationships in various metalloenzymes such as methane monooxygenase, cytochrome P450, heme oxygenase, dopamine -monooxygenase, and tyrosinase using extended Hückel calculations, DFT calculations, and QM/MM (quantum mechanical/molecular mechanical) calculations. Our recent interests include the enzymetic functions of dinuclear copper centers that are found in many oxygenation enezymes. The type-3 dinuclear copper centers are always found in 3 connection with the activation of O2. The O2-transporting hemocyanin as well as several O2-dependent oxidases (electron transfer and catalysis) and monooxygenases (transfer of one O from O2) are featured in this group. In my talk our QM/MM studies on dicopper oxygenation enzymes are presented by using whole-enzyme models of about 5000 atoms. One is the dicopper active site of particulate methane monooxygenase (pMMO) that catalyzes the hydroxylation of methane with dioxygen under physiological conditions, and the other one is the dicopper active site of tyrosinase that catalyzes the hydroxylation of monophenols to ortho-diphenols (cresolase activity) and the subsequent two-electron oxidation to ortho-quinones (catecholase activity) with dioxygen. Figure 1 shows a QM/MM optimized structure of the oxy form of tyrosinase. The (μ-2:2-peroxo)dicopper(II) species plays an essential role in a series of elementary processes mediated by the dicopper species of tyrosinase. Tyrosine QM region * His38 His190 * O His54 CuA CuB O His194 * His63 * * His216 * Fig. 1. Tyrosinase-substrate complex model with 4886 atoms. [1] K. Yoshizawa, Acc. Chem. Res., 39, 375-382 (2006). [2] K. Yoshizawa, Y. Shiota, J. Am. Chem. Soc., 128, 9873-9881 (2006). [3] T. Inoue, Y. Shiota, K. Yoshizawa, J. Am. Chem. Soc., 130, 16890-16897 (2008). .