Non-covalent Fc-Fab interactions significantly alter internal dynamics of an IgG1 antibody

Abstract

The fragment-antigen-binding arms (Fab1 and Fab2) in a canonical immunoglobulin G (IgG) molecule have identical sequences and hence are always expected to exhibit symmetric conformations and dynamics. Using long all atom molecular simulations of a human IgG1 crystal structure 1HZH, we demonstrate that the translational and rotational dynamics of Fab1 and Fab2 also strongly depend on their interactions with each other and with the fragment-crystallizable (Fc) region. We show that the Fab2 arm in the 1HZH structure is non-covalently bound to the Fc region via long-lived hydrogen bonds, involving its light chain and both heavy chains of the Fc region. These highly stable interactions stabilize non-trivial conformer states with constrained fluctuations. We observe subtle modifications in Fab1 dynamics in response to Fab2-Fc interactions that points to novel allosteric interactions between the Fab arms. These results yield novel insights into the inter- and intra-fragment motions of immunoglobulins which could help us better understand the relation between their structure and function.

Effects of N-glycans on the structure of human IgA2

“…Non-covalent interactions between the Fab and Fc regions have also been observed in IgG1 antibodies. These findings demonstrate the complex allosteric interactions that govern antibody dynamics and asymmetry (Natesan and Agrawal, 2022). The used approach is effective in modeling the intrinsic flexibility of antibodies and has been applied to characterize other types of immunoglobulins (Hodge et al, 2021;Belviso et al, 2022).…”

Heterogeneity in Disulfide Bond Reduction in IgG1 Antibodies Is Governed by Solvent Accessibility of the Cysteines

“…Qin et al [32] have previously shown that the stability of a disulfide bond primarily depends on (a) the distance between the sulfur atoms; (b) the orientations of the sulfur atoms defined in terms of angles Θ 1 and Θ 2 shown in Supplementary Figure S3; and (c) the solvent accessibility of the cysteine residues. We examined the role of these physical mechanisms using molecular dynamics simulations of full-length IgG1κ (VK3/VH3 germline) and IgG1λ (VL3/VH3 germline) mAbs, performed in implicit solvent conditions as described in the Materials and Methods section and detailed in our earlier publications [23,33]. Briefly, we used Discovery Studio to generate homology models for each molecule, using the 1HZH structure in RCSB PDB [34] as the template.…”