Catalysis on the coastline: theozyme,molecular dynamics,and free energy perturbation analysis of antibody 21D8 catalysis of the decarboxylation of 5-nitro-3-carboxybenzisoxazole |
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Authors: | Ujaque Gregori Tantillo Dean J Hu Yunfeng Houk K N Hotta Kinya Hilvert Donald |
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Institution: | Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Ave., Los Angeles, California 90095-1569, USA. |
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Abstract: | Antibody 21D8 catalyzes the decarboxylation of 5-nitro-3-carboxybenzisoxazole. The hapten used was designed to induce an antibody binding site with anion binders for the carboxylate, plus a nonpolar environment to accelerate decarboxylation. A recent X-ray crystal structure of 21D8 has shown that the binding pocket contains an array of both polar and charged residues. Nevertheless, 21D8 is able to catalyze a reaction that involves a decrease in polarity from reactant to transition state. The origins of this phenomenon were explored using various computational strategies-quantum mechanics, theozyme models, docking, molecular dynamics, free energy perturbation, and linear interaction energy-the combination of which has produced a consistent picture of catalysis. By partially desolvating the charged carboxylate, 21D8 manages to effect "catalysis on the coastline," without burying the carboxylate in a nonpolar region of the binding pocket. The results have implications for that broad class of enzyme and antibody catalyzed reactions that involve the conversion of a substrate with a relatively localized charge into a transition state with a highly dispersed charge. |
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