Computational dissection of the cooperative effects of Fc glycosylation and light chain isotype on IgG1::FcγRIIIa recognition

Monoclonal antibodies (mAbs) are complex biomolecular systems whose effector functions arise from the interplay of multiple structural and dynamic determinants. In IgG1, binding to Fcγ receptors, especially FcγRIIIa, is strongly influenced by Fc N-glycosylation at Asn297, while growing evidence suggests that light chain (LC) composition may also contribute to receptor recognition. However, the extent to which Fc glycosylation and LC isotype jointly shape the organization of the IgG1::FcγRIIIa complex remains unclear. Here, we used a computational workflow combining chimeric homology modeling and all-atom molecular dynamics (MD) simulations to investigate the cooperative effects of Fc core fucosylation and LC isotype on FcγRIIIa recognition. Two therapeutic IgG1 mAbs differing in LC composition (κ or λ) were modeled in both fucosylated and afucosylated glycoforms, and the resulting IgG1::FcγRIIIa complexes were analyzed to characterize conformational dynamics, interface stability, and interaction networks at atomistic resolution. Comparative analyses showed that both variables reshape the dynamic landscape of receptor engagement. Afucosylated variants displayed enhanced stabilization of the IgG1::FcγRIIIa interface and a more favorable interaction network, whereas core fucosylation was associated with reduced complex stability. In parallel, κ LC-containing antibodies adopted a more stable receptor-bound conformation than their λ counterparts, pointing to a previously underappreciated allosteric contribution of LC architecture to Fc-mediated recognition. Overall, these results provide an atomistic framework for understanding how Fc glycosylation and LC isotype cooperatively regulate IgG1::FcγRIIIa recognition. Beyond refining the mechanistic picture of Fc-mediated effector functions, this study supports the rational design of next-generation therapeutic antibodies with optimized functional properties.