Study on the S239D/I332E mutation effect on the kinetics of Fc–Fc receptor binding through transition complex theory

The S239D/I332E mutation in both chain A and chain B of Fc is widely employed to enhance the binding affinity of Fc to its receptor (FcγRIIIa). Despite its popularity in Fc mutation, the kinetic effect of this mutation has not been explored theoretically. This study delves into the impact of S239D and I332E mutations on the association rate between Fc and its receptor by employing computational modeling and transition complex theory. It was revealed that the double mutant exerts the most significant effect, followed by the S239D single mutant and then the I332E single mutant, as evidenced by their association rate constants. We also assessed the mutation effect on the dissociation rate constant indirectly by utilizing experimentally determined binding affinities and the estimated association rate constants. The mutation influence on dissociation outweighs its impact on association, although with varying degrees among the mutants. In particular, the double mutant demonstrated the highest impact on dissociation, while the effects were relatively weak for the two single mutants. These mutation effects on the kinetics of the Fc–Fc receptor interaction correlate with specific molecular interactions at the binding interfaces of the mutant complexes, providing valuable insights for the design of Fc–Fc receptor binding and contributing to our understanding of these crucial interactions in immunology.