Mechanism for antibody catalysis of the oxidation of water by singlet dioxygen
- 化学化工－已发表论文 
Wentworth et al. [Wentworth, P., Jones, L. H., Wentworth, A. D., Zhu, X. Y., Larsen, N. A., Wilson, I. A., Xu, X., Goddard, W. A., Janda, K. D., Eschenmoser, A. & Lerner, R. A. (2001) Science 293, 1806-1811] recently reported the surprising result that antibodies and T cell receptors efficiently catalyze the conversion of molecular singlet oxygen (O-1(2)) plus water to hydrogen peroxide (HOOH). Recently, quantum mechanical calculations were used to delineate a plausible mechanism, involving reaction of O-1(2) with two waters to form HOOOH (plus H2O), followed by formation of HOOOH dimer, which rearranges to form HOO-HOOO + H2O, which rearranges to form two HOOH plus O-1(2) or O-3(2). For a system with O-18 H2O, this mechanism leads to a 2.2:1 ratio of O-16:O-18 in the product HOOH, in good agreement with the ratio 2.2:1 observed in isotope experiments by Wentworth et al. In this paper we use docking and molecular dynamics techniques (HierDock) to search various protein structures for sites that stabilize these products and intermediates predicted from quantum mechanical calculations. We find that the reaction intermediates for production of HOOH from O-1(2) are stabilized at the interface of light and heavy chains of antibodies and T cell receptors. This inter Greek key domain interface structure is unique to antibodies and T cell receptors, but is not present in beta(2)-microglobulin, which does not show any stabilization in our docking studies. This result is consistent with the experimentally observed lack of HOOH production in this system. Our results provide a plausible mechanism for the reactions and provide an explanation of the specific structural character of antibodies responsible for this unexpected chemistry.