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

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.

Automated summary

In this study, long molecular simulations were used to investigate the interactions between Fab1, Fab2, and the Fc region in a human IgG1 crystal structure. The results revealed the importance of these interactions in determining the conformation and dynamics of the antibody. Specifically, the Fab2 arm was found to be non-covalently bound to the Fc region through long-lived hydrogen bonds, resulting in stable conformer states and influencing the dynamics of Fab1.