Loops from one V-region chain affect the conformations and dynamics of loops in the other chain

Summary

Loops from one V-region chain affect the conformations and dynamics of loops in the other chain (Guloglu and (1,2)). For example, light chain loops can affect the dynamics of CDRH3 (Guloglu and (1)). Longer CDRL1 loops and shorter CDRL3 loops correlate with restricted CDRH3 dynamics. In contrast, lengths of other loops had a lesser impact and were less dynamic albeit not entirely static. This is also consistent with observations from MD simulations (3). (2) show an example of strong epistasis between light chain residues that facilitate a reconfiguration of CDRH2.

Details

Only CDRH3 is flexible based on Metadynamics simulations on 8 antibody structures (Guloglu and (1)). The least flexible H3 loop out of those simulations is found in 45% of frames, whereas the most flexible ones never revisit the crystallized conformation.

See also

• Deep learning methods produce different CDRH3 conformers
• Light chain coherence
• Inclusion of adjacent loops can improve CDRH3 structural modeling

1.

Guloglu B, Deane CM. Specific attributes of the VL domain influence both the structure and structural variability of CDR-H3 through steric effects. Frontiers in Immunology. 2023;14. Available from: https://doi.org/10.3389/fimmu.2023.1223802

2.

Tharp CR, Catalano C, Khalifeh A, Ghaffari-Kashani S, Huang R, Kang G, et al. Biophysical trade-offs in antibody evolution are resolved by conformation-mediated epistasis. openRxiv; 2026. Available from: https://doi.org/10.64898/2026.03.12.711465

3.

Fernández-Quintero ML, Pomarici ND, Math BA, Kroell KB, Waibl F, Bujotzek A, et al. Antibodies exhibit multiple paratope states influencing VH–VL domain orientations. Communications Biology. 2020;3(1). Available from: https://doi.org/10.1038/s42003-020-01319-z