Computational modeling of the Fc$\alpha $RI receptor binding in the Fc$\alpha $ domain of the human antibody IgA: Normal Modes Analysis (NMA) study

Fc$\alpha $RI receptor binding in the Fc$\alpha $ domain of the antibody IgA triggers immune effector responses such as phagocytosis and antibody-dependent cell-mediated cytotoxicity in eukaryotic cells. Fc$\alpha $ is a dimer of heavy chains of the IgA antibody and each Fc$\alpha $ heavy chain which consisted of two immunoglobulin constant domains, C$_{\mathrm{H}}$2 and C$_{\mathrm{H}}$3, can bind one Fc$\alpha $RI molecule at the C$_{\mathrm{H}}$2-C$_{\mathrm{H}}$3 interface forming a 2:1 stoichiometry. Experimental evidences confirmed that Fc$\alpha $RI binding to the Fc$\alpha $ C$_{\mathrm{H}}$2-C$_{\mathrm{H}}$3 junction altered the kinetics of HAA lectin binding at the distant IgA1 hinge. Our focus in this research was to understand the conformational changes and the network of residues which co-ordinate the receptor binding dynamics of the Fc$\alpha $ dimer complex. Structure-based elastic network modeling was used to compute normal modes of distinct Fc$\alpha $ configurations. Asymmetric and un-liganded Fc$\alpha $ configurations were obtained from the high resolution crystal structure of Fc$\alpha $-Fc$\alpha $RI 2:1 symmetric complex of PDB ID 1OW0. Our findings confirmed that Fc$\alpha $RI binding, either in asymmetric or symmetric complex with Fc$\alpha $, propagated long-range conformational changes across the Fc domains, potentially also impacting the distant IgA1 hinge.