Kinked CDRH3 loops

Kinked CDRH3 are a conformational feature found in 80-90% of human antibodies and nearly 60% of camelid nanobodies (1,2). This occurs at the C-terminus of the loop and is dictated by germline use. Similar bends are found in other proteins, such as PDZ domains and peptidase C1 domains, that are involved in protein-protein interactions (1).

Ref (1) Ref (2)

Details

The precise definition by Weitzner et al uses the following two parameters:

• ${\tau }_{101}$: $C_{\alpha }$-$C_{\alpha }$-$C_{\alpha }$ pseudo-bond angle over the three C-terminal loop residues (Chothia 100X–101–102, IMGT 115-116-117).
• ${\alpha }_{101}$: $C_{\alpha }$-$C_{\alpha }$-$C_{\alpha }$-$C_{\alpha }$ pseudo-dihedral angle over the same three residues plus the next one (Chothia 103, IMGT 118).

Then, a two-parameter model is fit over these that includes a Gaussian component centered at ${\tau }_{101}101°$ (80% of structures) and a von Mises component centered at ${\alpha }_{101}39°$. This includes about 80% of structures in the PDB at the time of the Weitzner paper. Loops that fall into this component are considered kinked, while those that don’t are considered extended or straight.

Notes

• Axe-like CDRH3 loops

1.

Weitzner BD, Dunbrack RL, Gray JJ. The Origin of CDR H3 Structural Diversity. Structure. 2015;23(2):302–11. Available from: https://doi.org/10.1016/j.str.2014.11.010

2.

Bahrami Dizicheh Z, Chen I-L, Koenig P. VHH CDR-H3 conformation is determined by VH germline usage. Communications Biology. 2023;6(1). Available from: https://doi.org/10.1038/s42003-023-05241-y