Antibody-catalyzed oxy-cope rearrangement: mechanism and origins of catalysis and stereoselectivity from DFT quantum mechanics and flexible docking

Density functional theory using B3LYP and flexible ligand docking methods were used to investigate the complete potential surface for the uncatalyzed and the AZ28 antibody-catalyzed oxy-Cope reaction of 2,5-diaryl-1,5-hexadien-3-ol derivatives. The reaction mechanism is stepwise, involving a cyclohexane diyl intermediate. Theoretical deuterium isotope effects match well with those from experiment. Gas-phase transition structures show mixed preferences for the axial vs equatorial hydroxyl group, while solvation favors the axial isomer. Specific phenyl group conformations are shown to be critical to transition-state stabilization (by up to 15 kcal/mol), and the effective conformation is not that found in the hapten used to generate the germline and affinity-matured AZ28 catalytic antibodies. Docking studies support greater transition-state binding than reactant binding. Docking studies also predict the S stereoselectivity of mature AZ28 and suggest that binding modes quite different from those of the hapten might play a role in catalysis, with specific focus on ligand hydrogen bonding to Asp(H101).