Catalysis on the coastline: theozyme, molecular dynamics, and free energy perturbation analysis of antibody 21D8 catalysis of the decarboxylation of 5-nitro-3-carboxybenzisoxazole.
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.
Ujaque
Gregori
G
Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Ave., Los Angeles, California 90095-1569, USA.
Tantillo
Dean J
DJ
Hu
Yunfeng
Y
Houk
K N
KN
Hotta
Kinya
K
Hilvert
Donald
D
D000465:Algorithms; D017151:Antibodies, Catalytic / Q000737:chemistry*; D001666:Binding Sites, Antibody; D002384:Catalysis; D018360:Crystallography, X-Ray; D007555:Isoxazoles; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D055672:Static Electricity
D017151:Antibodies, Catalytic; D007555:Isoxazoles; C414687:abzyme 21D8; C070771:5-nitro-3-carboxybenzisoxazole