Molecular dynamics simulation study of the negative correlation in antibody AZ28-catalyzed oxy-cope rearrangement

The oxy-Cope rearrangement reaction in the antibody AZ28 is investigated using ab initio molecular orbital calculations and molecular mechanical molecular dynamics simulations. This antibody, AZ28, is known as one of the few systems where the mature catalytic antibody shows a negative correlation between the transition state analogue (TSA) binding affinity and the catalytic rate of the oxy-Cope rearrangement compared to the germ line catalytic antibody. The ab initio optimized structure shows that the transition state structure has a more planar configuration than the TSA. The favorable electrostatic interactions between AZ28 and the transition state analogue overcome the unfavorable van der Waals interactions; thus, AZ28 shows higher binding affinity for the TSA than the germ line. However, the AZ28 is not flexible enough to accept the relatively planar transition state structure. Because the lower flexibility causes poorer antibody-hapten interaction energies, the activation free energy of the oxy-Cope rearrangement becomes larger in the mature antibody than the germ line. We show that the differences in flexibility between the germ line and the mature form and the differences in structure between TSA and the transition state are the origin of the negative correlation in AZ28-catalyzed oxy-Cope rearrangement. The mutation of residue 34 of the light chain, 34(L), affects the binding free energies through the interresidue interaction because it is the closest to the hapten among the six mutatable residues. However, it does not affect the negative correlation.