Fc–FcγRI\nComplexes: Molecular Dynamics\nSimulations Shed Light on Ectodomain D3′s Potential Role in\nIgG Binding

FcγRI plays a crucial role in the effector function\nof IgG\nantibodies, interacting with the lower hinge region of IgG1 with nanomolar\naffinity. Binding occurs specifically in domain 2 (D2) of the FcγRI\nectodomain, while domain 3 (D3) is a flexible linker. The D3 domain\nis positioned away from the IgG binding site on the FcγRI and\ndoes not directly contact the Fc region. This study investigates the\nstructural and functional properties of FcγRI D3 using 200 ns\nclassical MD simulations of two models: (1) a full FcγRI ectodomain\ncomplex with Fc and (2) a truncated model excluding D3. Our findings\nsuggest that the D3 ectodomain provides additional structural flexibility\nto the FcγRI–Fc complex without altering the C backbone\nmotion or flexibility of the KHR binding motif in the FG loop. Critical\nresidues involved in binding and contributing to complex stability\nwere evaluated regarding changes in intramolecular interactions and\ndestabilization tendency upon D3 truncation. Truncation did not significantly\nalter interactions around glycan-interacting residues in Fc chains\nor FcγRI–Fc binding interfaces. These findings provide\nvaluable insights into the role of FcγRI D3 in modulating the\nstructural dynamics of the FcγRI–Fc complex. While D3\ndoes not directly contact Fc, its mobility and positioning may modulate\nthe receptor’s affinity, accessibility, and ability to bind\nIgG immune complexes. We suggest that a truncated FcγRI construct\nlacking the D3 domain may be a promising candidate for biosensor or\ncapturing agents’ development and optimization, offering improved\nperformance in IgG capture assays without compromising critical binding\ninteractions.