Molecular simulations to rationalize humanized Ab2/3H6 activity

The murine anti-idiotypic antibody 3H6 (Ab2/3H6) is directed against the human 2F5 antibody, which is capable of neutralizing HIV-1. Recently, four humanized Ab2/3H6models have been developed in order to reduce the risk of human anti-mouse antibody (HAMA) responses in case of administration to humans. In this study, molecular dynamics simulations were performed on these models as well as on the murine Ab2/3H6 in solution and bound to 2F5, in order to rationalize the differences in binding affinities of the models towards 2F5. Analysis of these simulations suggested that the orientation and dynamics of the residues TYR54 and TYR103 of the heavy chain of Ab2/3H6 play an important role in these differences. Subsequently, the contribution of these residues to the binding affinity was quantified by applying free energy calculations