IgG1 Fc - CD16a interaction_fucose

Description

Deciphering the Role of Core Fucosylation in IgG1 Fc–CD16a Binding Through All-Atom Simulations Core fucosylation of the IgG1 Fc N297 glycan is known to reduce binding affinity to the FcγRIIIa (CD16a) receptor and attenuate antibody-dependent cellular cytotoxicity (ADCC), yet the structural mechanisms underlying this effect remain incompletely understood. Here, we present a comprehensive molecular dynamics investigation of the Fc–CD16a complex across multiple glycoforms varying in fucosylation and galactosylation. Binding free energies calculated using MM-PBSA reveal that core fucosylation consistently reduces Fc–CD16a affinity, irrespective of single or dual fucosylation. Mechanistically, dual fucosylation increases inter-glycan contacts between the Fc N297 glycans, constraining their conformational sampling. Concurrently, the CD16a N162 glycan exhibits expanded conformational heterogeneity, indicating receptor destabilization. These glycan-mediated perturbations also impact the protein conformations as dual fucosylated systems display reduced protein–protein contact frequencies and redistribution of energetically significant residues away from the binding interface, particularly within the CD16a D1 domain. Potential of mean force analyses further demonstrate that dual afucosylated complexes adopt compact, well-defined conformational basins, whereas dual fucosylation promotes diffuse and less stable receptor orientations. Dynamic cross-correlation analysis reveals diminished inter-domain coupling in dual fucosylated systems, indicating disruption of coordinated motions across the Fc–CD16a interface. Together, our results establish that core fucosylation weakens Fc–CD16a binding, the impact of dual fucosylation on glycan confinement, receptor destabilization, altered interfacial energetics, and impaired dynamic coupling is more significant than single fucosylation. These findings provide a mechanistic framework for understanding glycoengineering strategies that enhance antibody effector function. All-atom MD simulation trajectories used in this study are shared here.

Institutions

• Northeastern University

  Massachusetts, Boston

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