Quantum chemical study on the affinity maturation of 48G7 antibody

In this study, we calculate the binding energies of hapten with the germline and mature forms of the 48G7 antibody. The energies are obtained using a combined method of a linear-scaling quantum chemical calculation (known as MOZYME) and a continuum solvent model (known as COSMO). The calculations successfully reproduced the experimental fact that the binding energy increases on going from the germline to mature forms. Detailed analysis indicated that such affinity improvement is mainly due to the electrostatic improvement caused by the following mutations: Asp/His L 55, Glu/Lys H 42, Asn/Asp H 57, Gly/Asp H 66, Asn/Lys H 77 in the heavy (H) and light (L) chains. An interesting finding is that the intermolecular charge transfer and electronic polarization effects significantly contribute to the binding energy between the hapten and the antibody. Furthermore, the frontier orbitals of the antibody are localized at the hapten binding site. These results imply that the orbital interactions play an important role in stabilizing the antibody-hapten complexes. In conclusion, quantum mechanical calculation such as MOZYME is indispensable for in silico drug screening.