Journal
SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-022-13370-3
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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.
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.
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