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

• Published in: Scientific reports Vol. 12; no. 1; p. 9321
• Main Authors: Natesan, Ramakrishnan, Agrawal, Neeraj J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/2410; 631/114/2411; 631/57/2266; 639/166/985; 639/766/747; Allosteric properties; Antibodies; Antigens; Crystal structure; Fab; Humanities and Social Sciences; Hydrogen bonding; Hydrogen bonds; Immunoglobulin G; Immunoglobulins; multidisciplinary; Normal distribution; Science; Science (multidisciplinary); Simulation; Structure-function relationships
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-13370-3

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.