The Origin of CDR H3 Structural Diversity

Abstract

Antibody CDR H3 loops are critical for adaptive immunological functions. Although the other five CDR loops adopt predictable canonical structures, H3 conformations have proven unclassifiable, other than an unusual C-terminal “kink” present in most antibodies. To determine why the majority of H3 loops are kinked and to learn whether non-antibody proteins have loop structures similar to H3, we searched a set of 15,679 high-quality non-antibody structures for regions geometrically similar to the residues immediately surrounding the loop. By incorporating the kink into our search, we identified 1,030 H3-like loops from 632 protein families. Some protein families, including PDZ domains, appear to use the identified region for recognition and binding. Our results suggest the kink is conserved in the immunoglobulin heavy chain fold because it disrupts the β-strand pairing at the base of the loop. Thus, the kink is a critical driver of the observed structural diversity in CDR H3.

Modeling and docking of antibody structures with Rosetta

“…The H3 loop is first completely remodeled in the context of the antibody framework using the next-generation KIC (NGK) loop modeling protocol 21 . For speed, the H3 loop side chains are each reduced to a single low-resolution pseudo-atom, and to ensure sampling of the C-terminal kink conformation 32 , atomic constraints are applied to the governing score function 33 . For subsequent high-resolution refinement, the all-atom CDR H3 side chains are recovered, all CDR side chains are repacked, and the CDR side chains and backbones are minimized.…”

Role of Non-local Interactions between CDR Loops in Binding Affinity of MR78 Antibody to Marburg Virus Glycoprotein

“…A straight conformation of HCDR3 loop with H-bond ladder like in MR78 is infrequent in antibody structures as the majority of the long HCDR3 loops (with >14 amino acids) adopt non-straight (bent or broad) conformations(Tsuchiya and Mizuguchi, 2016). The position of Gly111 residue is more toward the N terminus of the HCDR3 loop, as is expected for loops with a bulged torso conformation(Weitzner et al, 2015). …”

“…The dihedral angle α 101 positions the kink relative to the framework of the antibody and the bond angle τ 101 measures the degree of the kink in the torso region. The study showed that the distribution of τ 101 measured for antibody structures is centered at 39° and the distribution of α 101 is centered at 101° (Weitzner et al, 2015). …”

Generation of Antibody Diversity

“…Especially the diversity of the CDR3 (complementarity-determining region), which has a huge influence on the antigen binding [9,10], is affected with high frequency by this process, because of its position between the V and J gene segments in the heavy chain and between the V and J gene segments in the light chain. The CDR1 and CDR2 loops are not affected by junctional diversity, because of their position in the V gene segment of the heavy and light chain.…”