Computational Modeling of Antibody and T-Cell Receptor (CDR3 Loops)

Antibodies and T-cell receptors have been a subject of much interest due to their central role in the immune system and their potential applications in several biotechnological and medical applications from cancer therapy to vaccine development. A unique feature of these two lymphocyte receptors is their ability to bind a huge variety of different (pathogen) targets. This ability stems from six short loops in the binding domain that have hypervariable sequence due to genetic recombination mechanism. Particularly one of these loops, the third complementarity determining region (CDR3), has the highest sequence variability and a dominant role in binding the target. However, it has also been proven the most difficult to be modeled structurally, which is vitally important for downstream tasks such as binding prediction. This difficulty stems from its variability in sequence that both reduces the possibility of finding homologues and introduces unique structural features in the loop. We present here a general protocol for modeling such loops in antibodies and T-cell receptors. We also discuss the difficulties in loop modeling and the advantages and limitations of different modeling methods.