Following the discoveries of catalytic activity in antibodies raised to transition state analogs, it has become clear that antibodies can catalyze a wide range of chemical reactions that are catalyzed in nature by enzymes. Recent work has focused on chemical reactions that do not occur in natural systems, such as Diels-Alder reactions, which, however, can occur chemically. Catalytic antibodies have the advantage that they can also catalyze reactions that are chemically disfavored due to steric hindrance. It is proposed to study antibody catalysis of disfavored reactions, beginning with the dissection of the catalysis of a highly disfavored syn elimination reaction to form a cis olefin. The second major aim is to elicit antibodies of improved function by utilizing mechanism-based induction. We will be utilizing considerable expertise and experience in the laboratory in hapten design and antibody production and characterization. It is anticipated that fruitful collaborations with the other three projects will follow the beginnings outlined in this proposal, and that structural work will commence shortly using both X-ray crystallography and NMR on several of the catalytic antibodies produced as part of this project. This work will lead to a better understanding of the structural basis of antibody catalysis, and it will give valuable insights into the nature of catalysis in solution in general.
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