A Computational Strategy for the Rapid Identification and Ranking of Patient‐Specific T cell Receptors Bound to Neoantigens

Abstract T cell receptor (TCR) recognition of a peptide–major histocompatibility complex (pMHC) is crucial for adaptive immune response. The identification of therapeutically relevant TCR‐pMHC protein pairs is a bottleneck in the implementation of TCR‐based immunotherapies. The ability to computationally design TCRs to target a specific pMHC requires automated integration of next‐generation sequencing, protein–protein structure prediction, molecular dynamics, and TCR ranking. A pipeline to evaluate patient‐specific, sequence‐based TCRs to a target pMHC is presented. Using the three most frequently expressed TCRs from 16 colorectal cancer patients, the protein–protein structure of the TCRs to the target CEA peptide–MHC is predicted using Modeller and ColabFold. TCR‐pMHC structures are compared using automated equilibration and successive analysis. ColabFold generated configurations require an ≈2.5× reduction in equilibration time of TCR‐pMHC structures compared to Modeller. The structural differences between Modeller and ColabFold are demonstrated by root mean square deviation (≈0.20 nm) between clusters of equilibrated configurations, which impact the number of hydrogen bonds and Lennard‐Jones contacts between the TCR and pMHC. TCR ranking criteria that may prioritize TCRs for evaluation of in vitro immunogenicity are identified, and this ranking is validated by comparing to state‐of‐the‐art machine learning‐based methods trained to predict the probability of TCR‐pMHC binding.