T-cell receptor structures and predictive models reveal comparable alpha and beta chain structural diversity despite differing genetic complexity

Abstract

T-cell receptor (TCR) structures are currently under-utilised in early-stage drug discovery and repertoire-scale informatics. Here, we leverage a large dataset of solved TCR structures from Immunocore to evaluate the current state-of-the-art for TCR structure prediction, and identify which regions of the TCR remain challenging to model. Through clustering analyses and the training of a TCR-specific model capable of large-scale structure prediction, we find that the alpha chain VJ-recombined loop (CDRA3) is as structurally diverse and correspondingly difficult to predict as the beta chain VDJ-recombined loop (CDRB3). This differentiates TCR variable domain loops from the genetically analogous antibody loops and supports the conjecture that both TCR alpha and beta chains are deterministic of antigen specificity. We hypothesise that the larger number of alpha chain joining genes compared to beta chain joining genes compensates for the lack of a diversity gene segment. Overall, our study demonstrates that valuable structure-function relationships can lie in alpha chains despite their simpler junctions. We also provide over 1.5M predicted TCR structures to enable repertoire structural analysis and elucidate strategies towards improving the accuracy of future TCR structure predictors.