TRANSITION-STATE OF THE BASE-PROMOTED RING-OPENING OF ISOXAZOLES - THEORETICAL PREDICTION OF CATALYTIC FUNCTIONALITIES AND DESIGN OF HAPTENS FOR ANTIBODY-PRODUCTION

In previous research, Hilvert and co-workers developed an antibody whi ch catalyzes the decomposition of a nitrobenzisoxazole with a rate > 1 0(8) times faster than the acetate-catalyzed reaction in water. Quantu m mechanical calculations were carried out on a model system, the reac tion of isoxazole with formate. The orientation of the carboxylate gro up has a significant effect on the rate, Complexation of the formate b ase by one water retards the reaction by approximately 5 kcal/mol; hen ce desolvation of the catalytic base could account for as much as four orders of magnitude in reaction rate. It was also determined that hyd rogen-bonding to the forming oxide could potentially lead to greater r ate acceleration. The gas phase activation barriers predict that water is the most effective general acid, lowering the activation energy by 9.5 kcal/mol. Methanol and formic acid are also effective, lowering t he activation energy by 7.5 and 7.8 kcal/mol, respectively. Our calcul ations suggest that the combined effects of proper base orientation an d acid catalysis could lead to an additional factor of 10(5)-10(6) inc rease in rate acceleration. Based on these results, various new hapten s were proposed. Each was quantitatively assessed for similarity with the located transition states to predict their potential as successful haptens.