Origins and predictions of stereoselective antibody catalysis: theoretical analysis of Diels-Alder catalysis by 39A11 and its germ-line antibody.

The binding of enantiomeric haptens and transition states by the Schultz Diels-Alderase antibody 39A11 and its germ-line antibody were studied theoretically. The mechanisms by which one hapten and one transition state stereoisomer is recognized selectively are explored with docking simulations and quantum mechanical models. Transition states of the relevant Diels-Alder reaction were located with density functional theory. A prediction is made that the stereoselectivity of 39A11 will be achieved by two strategically placed hydrogen bonds and pi-stacking interactions of the maleimide with a binding-site tryptophan, arranged so as to coordinate one enantiomeric transition state. Binding of other ligands by antibody 39A11 and the germ-line antibody has also been investigated. The polyspecific nature of 39A11 and its germ-line precursor was found to originate from the general ability of the binding pockets to achieve hydrophobic binding of small organic substrates. Comparison of the highly homologous progesterone and Diels-Alderase antibodies (DB3, 1E9, and 39A11) highlights the fact that differences of several key residues in the binding pockets are sufficient to confer selectivity for different antigens.