Free energy perturbation approach for the rational engineering of the antibody for human hepatitis B virus.

HzKR127 is the humanized monoclonal antibody effective for the neutralization of human hepatitis B virus. By means of the free energy perturbation (FEP) calculations based on molecular dynamic (MD) simulations, we examine the mutation-induced variations in the energetic and structural features associated with the interactions between HzKR127 and its antigen. N58A, Y96A, D97A, and D97A/Y102A mutants of HzKR127 are taken in account in this study for which the experimental data for relative efficacies with respect to the wild-type antibody are available. The results of the present MD-FEP simulation studies show that in order to enhance the affinity for the antigen, the engineering of HzKR127 should be made in such a way as to promote the dynamic stability of the overall protein conformation and that of the translational motion of the antigen in the antibody-antigen complex. The relative binding free energies of the four mutant antibodies obtained from MD-FEP calculations compare pretty well with the experimental mutagenesis data with the associated squared correlation coefficient of 0.96. This indicates that MD-FEP calculations may serve as a useful computational tool for rational antibody engineering. Discussed in detail are the differences in the structural features of antibody-antigen interactions between the wild-type and the mutant antibodies that are responsible for the change in binding affinities for the antigen.