Computational Modeling of the FcαRI Receptor Binding in the Fcα Domain of the Human Antibody IgA: Corse-Grained Molecular Dynamics (MD) Methods

Abstract

FcαRI receptor binding in the Fcα domain of the antibody IgA triggers immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release in eukaryotic cells. Fcα is a dimer of heavy chains of the IgA antibody and each Fcα heavy chain which consisted of two immunoglobulin constant domains, CH2 and CH3, can bind one FcαRI molecule at the CH2-CH3 interface forming a 2:1 stoichiometry which is unique to the human IgA. Experimental evidences confirmed that FcαRI binding to the Fcα CH2-CH3 junction altered the kinetics of HAA lectin binding at the distant IgA1 hinge and distant Fab region.Given the importance of residues near the CH2-CH3 junction for receptor binding that were predicted experimentally by binding energetic analysis, our focus in this computational research was to understand the conformational changes and the residue-pairs in long-range communication which co-ordinate the receptor binding dynamics of the Fcα dimer complex.We computed the principal collective motions by using the corse-grained structure based molecular dynamics trajectories performed on the high resolution crystal structure of Fcα-FcαRI 2:1complex of PDB ID 1OW0 to understand the functional dynamics in Fcα. We used three distinct Fcα conformations namely free Fcα, Fcα-FcαRI 1:1 asymmetric and Fcα-FcαRI 2:1 symmetric complexes to comparatively study the functional dynamics induced upon receptor binding.Our findings confirmed that FcαRI binding, either in asymmetric or symmetric complex with Fcα, propagated long-range conformational changes across the Fc domains, potentially also impacting the hinge and Fab regions.Key words: IgA antibody, single-basin structure-based coarse grain MD simulation, principal component modes, long-range interaction, ligand-induced conformational changes