Structure-based prediction of T cell receptor recognition of unseen epitopes using TCRen

Nature Computational Science. 2024. Vol. 4. No. 7. P. 510–521.

Karnaukhov V. K., Shcherbinin D. S., Chugunov A. O., Chudakov D. M., Efremov R., Zvyagin I. V., Shugay M.

T cell receptor (TCR) recognition of foreign peptides presented by major histocompatibility complex protein is a major event in triggering the adaptive immune response to pathogens or cancer. The prediction of TCR-peptide interactions has great importance for therapy of cancer as well as infectious and autoimmune diseases but remains a major challenge, particularly for novel (unseen) peptide epitopes. Here we present TCRen, a structure-based method for ranking candidate unseen epitopes for a given TCR. The first stage of the TCRen pipeline is modeling of the TCR-peptide-major histocompatibility complex structure. Then a TCR-peptide residue contact map is extracted from this structure and used to rank all candidate epitopes on the basis of an interaction score with the target TCR. Scoring is performed using an energy potential derived from the statistics of TCR-peptide contact preferences in existing crystal structures. We show that TCRen has high performance in discriminating cognate versus unrelated peptides and can facilitate the identification of cancer neoepitopes recognized by tumor-infiltrating lymphocytes.

Keywords: компьютерное моделирование, computer simulations, TCR-peptide binding, residue-residue potentials, связывание TCR-пептид, потенциалы остаток-остаток