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HaC-Si CH3

Figure 7 Cationic cyclization. (Modified from Schultz PG and Lerner RA (1995) Molecular diversity to catalysis: lessons from the immune system. Science 269: 1835-1842.)

conformation is determined by a few key residues. The area of interaction between the antigen and antibody may be relatively flat and extensive for protein antigen binding to an antibody (700-750 A2), whereas in the case of small organic molecules the binding may occur by way of clefts whose volumes are in excess of 600A3. For small organic molecules the dissociation constant of the antibody-antigen complex ranges from 10 4 to 10~"'m, which if totally coupled to drive a chemical transformation would provide a free energy change up to 15 kcal m sufficient to promote most reactions in aqueous solution. The binding of antigen does not result in a global conformational change in the antibody. Rather, the union is accommodated by conformational adjustments in the specific amino acid side-chains that improve the initial binding interactions of hydrogen bonds, van der Waals and electrostatic forces. For a series of catalytic antibodies that were induced by phosphonate haptens (Figure 6) and hydrolyze esters, the activc site structures arc surprisingly congruent, suggesting the immunological response despite its diversity is tightly programmed by the chemical nature of the hapten. In general the crystallographic studies of catalytic antibodies show the bound hapten has induced antibodies that provide a three-dimensional arrangement of critical residues which resemble that found in enzymes of analogous activity. Although specific transition stare binding is a feature of any enzyme or catalytic antibody, there is no assurance that the combining site has side residues suitable for efficient catalysis. From crystallographic studies of both the catalytic antibody and enzyme that catalyze the Claisen rearrangement of chorismate to prephenate, the active sites of both provide environments that complement the bound transition state analog (Figure 12). The 104 difference in catalytic efficiency may be more a matter of degree, as the enzyme apparently provides v°"\\ //

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