Identification of the cognate peptide-MHC target of T cell receptors using molecular modeling and force field scoring

Esteban Lanzarotti, Paolo Marcatili, Morten Nielsen*

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

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    Interactions of T cell receptors (TCR) to peptides in complex with MHC (p:MHC) are key features that mediate cellular immune responses. While MHC binding is required for a peptide to be presented to T cells, not all MHC binders are immunogenic. The interaction of a TCR to the p:MHC complex holds a key, but currently poorly comprehended, component for our understanding of this variation in the immunogenicity of MHC binding peptides. Here, we demonstrate that identification of the cognate target of a TCR from a set of p:MHC complexes to a high degree is achievable using simple force-field energy terms. Building a benchmark of TCR:p:MHC complexes where epitopes and non-epitopes are modelled using state-of-the-art molecular modelling tools, scoring p:MHC to a given TCR using force-fields, optimized in a cross-validation setup to evaluate TCR inter atomic interactions involved with each p:MHC, we demonstrate that this approach can successfully be used to distinguish between epitopes and non-epitopes. A detailed analysis of the performance of this force-field-based approach demonstrate that its predictive performance depend on the ability to both accurately predict the binding of the peptide to the MHC and model the TCR:p:MHC complex structure. In summary, we conclude that it is possible to identify the TCR cognate target among different candidate peptides by using a force-field based model, and believe this works could lay the foundation for future work within prediction of TCR:p:MHC interactions.
    Original languageEnglish
    JournalMolecular Immunology
    Pages (from-to)91-97
    Number of pages7
    Publication statusPublished - 2018


    • Antigens/Peptides/Epitopes
    • MHC
    • Modelling
    • Pipeline
    • T cell receptor


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