Molecular Dynamics Simulations Reveal Interactions of an IgG1 Antibody With Selected Fc Receptors

In a survey of novel interactions between an IgG1 antibody and different Fc gamma receptors (Fc gamma R), molecular dynamics simulations were performed of interactions of monoclonal antibody involved complexes with Fc gamma Rs. Free energy simulations were also performed of isolated wild-type and substituted Fc regions bound to Fc gamma Rs with the aim of assessing their relative binding affinities. Two different free energy calculation methods, Molecular Mechanical/Generalized Born Molecular Volume (MM/GBMV) and Bennett Acceptance Ratio (BAR), were used to evaluate the known effector substitution G236A that is known to selectively increase antibody dependent cellular phagocytosis. The obtained results for the MM/GBMV binding affinity between different Fc gamma Rs are in good agreement with previous experiments, and those obtained using the BAR method for the complete antibody and the Fc-Fc gamma R simulations show increased affinity across all Fc gamma Rs when binding to the substituted antibody. The Fc gamma RIIa, a key determinant of antibody agonistic efficacy, shows a 10-fold increase in binding affinity, which is also consistent with the published experimental results. Novel interactions between the Fab region of the antibody and the Fc gamma Rs were discovered with this in silico approach, and provide insights into the antibody-Fc gamma R binding mechanism and show promise for future improvements of therapeutic antibodies for preclinical studies of biological drugs.

Automated summary

The study used molecular dynamics simulations and free energy simulations to assess interactions between antibodies and Fcγ receptors, discovering novel effects that enhance antibody-dependent cellular phagocytosis. Results obtained through different methods were consistent with previous experiments, revealing new interactions in the antibody-Fcγ receptor binding mechanism.