The goal of this research project is to understand the mechanism by which antibody catalysts accelerate the reaction and induce stereoselectivity. Subsidiary goals are to determine experimentally the absolute stereochemistries of Diels-Alder adducts obtained in these reactions, to determine relationships between amino acid sequences and binding site structures of different catalytic antibodies, and to develop methods for the calculation of antibody binding and catalysis. The stereoselectivity of Diels-Alder catalysis by antibodies is very high, but the directions of enantioselectivity and sometimes even diastereoselectivity are unknown. We will establish experimentally the stereochemistries of these reactions, develop understanding of the origins of stereoselectivity and catalysis through modeling, compare the immune response to different types of haptens and the binding sites produced by the immune system to achieve these catalytic functions, and predict how more effective functionalized antibody catalysts can be developed. The research will involve both experimental and computational studies designed to reveal the basic organic chemistry of antibody catalysis, and the development of computational methods to achieve better methods for the exploration of antibody structures and binding by the immune system.
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| Zhu, Xueyong; Heine, Andreas; Monnat, Frederic et al. (2003) Structural basis for antibody catalysis of a cationic cyclization reaction. J Mol Biol 329:69-83 |
| Cannizzaro, Carina E; Ashley, Jon A; Janda, K D et al. (2003) Experimental determination of the absolute enantioselectivity of an antibody-catalyzed Diels-Alder reaction and theoretical explorations of the origins of stereoselectivity. J Am Chem Soc 125:2489-506 |
| Green, N S; Reisler, E; Houk, K N (2001) Quantitative evaluation of the lengths of homobifunctional protein cross-linking reagents used as molecular rulers. Protein Sci 10:1293-304 |
