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Mechanism for antibody catalysis of the oxidation of water by singlet dioxygen

Datta, Deepshikha and Vaidehi, Nagarajan and Xu, Xin and Goddard, William A., III (2002) Mechanism for antibody catalysis of the oxidation of water by singlet dioxygen. Proceedings of the National Academy of Sciences of the United States of America, 99 (5). pp. 2636-2641. ISSN 0027-8424. PMCID PMC122400. doi:10.1073/pnas.052709399.

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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 (^1O_2) plus water to hydrogen peroxide (HOOH). Recently, quantum mechanical calculations were used to delineate a plausible mechanism, involving reaction of ^1O_2 with two waters to form HOOOH (plus H_2O), followed by formation of HOOOH dimer, which rearranges to form HOO—HOOO + H_2O, which rearranges to form two HOOH plus ^1O_2 or ^3O_2. For a system with ^(18)O H_2O, this mechanism leads to a 2.2:1 ratio of ^(16)O:^(18)O 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 ^1O_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 β2-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.

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Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2002 National Academy of Sciences. Contributed by William A. Goddard III, December 31, 2001. We thank Richard Lerner for suggesting this problem and Albert Eschenmoser, Paul Wentworth, Anita Wentworth, Lyn Jones, and Kim Janda for helpful discussions. We also thank Xueyong Zhu, Nicholas Larsen, and Ian Wilson for access to their 1.2-Å structure for the chimeric Fab antibody before publication. This research was funded by National Institutes of Health Grant HD 36385-02. The facilities of the Materials and Process Simulation Center used in these studies were funded by National Science Foundation–Major Research Instrumentation, Defense University Research Instrumentation Program (Army Research Office and Office of Naval Research), and the Beckman Institute. In addition, the Materials and Process Simulation Center is funded by grants from Department of Energy–Accelerated Strategic Computing Initiative–Academic Strategic Alliances Program, Army Research Office–Multidisciplinary University Research Initiative, National Institutes of Health, National Science Foundation, Avery–Dennison, Asahi Chemical, Chevron, 3M, Dow Chemical, Nippon Steel, Seiko-Epson, and Kellogg’s. These calculations were made under a SUR Grant from IBM.
Funding AgencyGrant Number
NIHHD 36385-02
Army Research Office (ARO)UNSPECIFIED
Office of Naval Research (ONR)UNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Dow Chemical CompanyUNSPECIFIED
Issue or Number:5
PubMed Central ID:PMC122400
Record Number:CaltechAUTHORS:20141120-095436298
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Official Citation:Datta, D., Vaidehi, N., Xu, X., & Goddard, W. A. (2002). Mechanism for antibody catalysis of the oxidation of water by singlet dioxygen. Proceedings of the National Academy of Sciences, 99(5), 2636-2641. doi: 10.1073/pnas.052709399
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:51995
Deposited By: Jason Perez
Deposited On:20 Nov 2014 19:34
Last Modified:10 Nov 2021 19:19

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