Abstract
FcγRI plays a crucial role in the effector function of IgG antibodies, interacting with the lower hinge region of IgG1 with nanomolar affinity. Binding occurs specifically in domain 2 (D2) of the FcγRI ectodomain, while domain 3 (D3) is a flexible linker. The D3 domain is positioned away from the IgG binding site on the FcγRI and does not directly contact the Fc region. This study investigates the structural and functional properties of FcγRI D3 using 200 ns classical MD simulations of two models: (1) a full FcγRI ectodomain complex with Fc and (2) a truncated model excluding D3. Our findings suggest that the D3 ectodomain provides additional structural flexibility to the FcγRI-Fc complex without altering the C backbone motion or flexibility of the KHR binding motif in the FG loop. Critical residues involved in binding and contributing to complex stability were evaluated regarding changes in intramolecular interactions and destabilization tendency upon D3 truncation. Truncation did not significantly alter interactions around glycan-interacting residues in Fc chains or FcγRI-Fc binding interfaces. These findings provide valuable insights into the role of FcγRI D3 in modulating the structural dynamics of the FcγRI-Fc complex. While D3 does not directly contact Fc, its mobility and positioning may modulate the receptor's affinity, accessibility, and ability to bind IgG immune complexes. We suggest that a truncated FcγRI construct lacking the D3 domain may be a promising candidate for biosensor or capturing agents' development and optimization, offering improved performance in IgG capture assays without compromising critical binding interactions.