Considerable progress was made in the previous grant period in a diverse group of projects. The program now focuses closely on fundamental problems of structure and chemistry of catalytic antibodies, and several of the proposed projects are concerned with the potential for engineering of these versatile molecules for improved or altered catalytic function. Antibody catalysis offers unprecedented opportunities for design of novel and highly specific biological catalysts for applications in medicine and chemistry, including tailoring of the substrate, mechanism and products of chemical reactions. The proposed work will benefit immeasurably from the close scientific ties between the Principal Investigators. The Program Director, Dr. Lerner, building on considerable experience as one of the original discoverers of catalysis by antibodies, proposes in Project 1 to investigate, together with Dr. Janda, the catalysis of disfavored transformations and to use mechanism-based induction to generate improved antibody catalysts. In Project 2, Drs. Wright and Dyson will focus primarily on the solution behavior of a single well-characterized catalytic antibody, using NMR spectroscopy to probe in detail the structure and dynamics of binding and catalysis. The conformation of bound substrates in a number of catalytic antibodies is also an important aim of this project. Dr. Wilson proposes in Project 3 to determine the X- ray crystal structures of a large number of catalytic antibodies in order to understand the role of desolvation, acid-base catalysis, strain, proximity effects and stabilization of transition states in their catalytic mechanism. In Project 4, Dr. Barbas will utilize phage display of an antibody repertoire to select for antibodies with specific catalytic functions. A core is proposed for support of both the biochemical and structural projects. Strong ties are present between the individual projects. The two structural projects have specific aims directly related to the work of the more biochemical projects based on excellent past collaborations. It is a measure of the collegial atmosphere fostered at The Scripps Research Institute that all of the Principal Investigators have published with their colleagues on this grant, in some cases for a number of years. The Scripps Research Institute is unique as a site for this research. The Principal Investigators are also uniquely qualified to carry out the research, being in many cases the pioneers of the techniques they propose to use, and all are leaders in their respective fields. We anticipate that the research for this program project in the next grant period will produce as many novel and useful insights into the biology and chemistry of catalytic antibodies (and by extension other catalysts) as it has done previously in the discovery of phage technology and of the catalytic antibodies themselves.
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