Theoretical investigation of the origins of catalysis of a retro-Diels-Alder reaction by antibody 10F11

The antibody 10F11 catalyzes a retro-Diels-Alder reaction that forms HNO. Deductions about the mechanism of catalysis were made by Reymond, Baumann et al. from X-ray crystal structures and from kinetic measurements for mutated antibodies. We report a study of these reactions with quantum mechanical methods and a study of the substrate and transition state binding to the active site of the antibody 10F11 using density functional theory and empirical docking methods. We have quantitated the likely contributions to catalysis of three residues identified as possible causes of catalysis: Trp H104, Phe H101, and Ser H100. Trp H104 can make a significant contribution to catalysis through dispersive interactions (pi-stacking aromatic-aromatic stabilization). On its own, Phe H101 makes only a small contribution to catalysis. When both aromatic residues are present, they act cooperatively and can make greater contributions to catalysis than expected for each residue alone. Ser H100 and the backbone NH of Phe H101 are expected to act through hydrogen bonding to speed up the reaction, but our calculations suggest that they make only a small contribution to catalysis. Reymond's studies suggest that the hydrogen-bonding network may be mediated through a water molecule in the binding site.