Effect of Fc core fucosylation and light chain isotype on IgG1 flexibility

N-glycosylation plays a key role in modulating the bioactivity of monoclonal antibodies (mAbs), as well as the light chain (LC) isotype can influence their physicochemical properties. However, investigating the impact of such features on mAbs conformational behavior is a big challenge, due to the very high flexibility of these biomolecules. In this work we investigate, by accelerated molecular dynamics (aMD), the conformational behavior of two commercial immunoglobulins G1 (IgG1), representative of kappa and lambda LCs antibodies, in both their fucosylated and afucosylated forms. Our results show, through the identification of a stable conformation, how the combination of fucosylation and LC isotype modulates the hinge behavior, the Fc conformation and the position of the glycan chains, all factors potentially affecting the binding to the Fc gamma Rs. This work also represents a technological enhancement in the conformational exploration of mAbs, making aMD a suitable approach to clarify experimental results. Classical and accelerated molecular dynamics simulations reveal how core fucosylation in the IgG1 Fc glycan and the light chain isotype modulate the conformational behavior of the hinge and Fab domains and dynamics of IgG1 antibodies.

Automated summary

N-glycosylation and light chain isotype play important roles in modulating the conformational behavior of monoclonal antibodies. Through accelerated molecular dynamics simulations, this study reveals how fucosylation and light chain isotype influence the hinge behavior, Fc conformation, and glycan chain position, factors that potentially affect the binding to Fc gamma receptors. Moreover, this work demonstrates the suitability of accelerated molecular dynamics as an approach to elucidate experimental results on antibody conformation.