(508e) Identification of CDR H3-Like Loop Conformations in Non-Immunoglobulin Proteins

The third complementarity-determining region loop on the immunoglobulin heavy chain (CDR H3) often provides a large portion of the antigen-binding contacts, providing motivation for antibody structure prediction algorithms to model this loop accurately. Despite significant effort, H3 structure prediction has remained elusive. One common strategy for loop modeling in non-antibody proteins is to find template loops with similar anchor positions, identical sequence length, and similar amino acid sequences. Because of the genetic mechanism that gives rise to the H3 loop, it is unclear whether their conformations are unique to antibodies. Although the other five CDR loops (L1, L2, L3, H1 and H2) have been shown to adopt canonical structures that can be reliably predicted by loop length and chain sequence, H3 conformations have proven to be unclassifiable, save for the fact that the majority contain an unusual “kink” or “bulge” at the C-terminal end of the loop. We set out to determine whether this feature is observed in other proteins, and if so, whether it confers structural properties similar to those observed in CDR H3. To that end, we searched a set of high-quality non-antibody structures for regions that match the geometry of the residues immediately surrounding the loop. By incorporating the C-terminal “kink”/“bulge” constraint into our search, we were able to identify a set of over 2,500 non-antibody loops that share a number of structural properties with H3 loops, namely: (1) position and prevalence of local structural features such as beta turns; (2) existence of non-antibody loops with RMSDs within 2.0 Å of nearly all H3 loops of length ≤ 15; (3) greater than expected occurrence of a salt bridge across the base of the loop. These results suggest that CDR H3 is similar to non-antibody loops, thus providing a set of templates that can be used to find starting structures for H3 loop structure prediction and design.