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

• Published in: Molecular immunology 2018-02, Vol.94, p.91-97
• Main Authors: Lanzarotti, Esteban, Marcatili, Paolo, Nielsen, Morten
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigen-Antibody Complex - chemistry; Antigen-Antibody Complex - immunology; Antigen-Antibody Complex - metabolism; Antigens/Peptides/Epitopes; Epitopes - chemistry; Epitopes - immunology; Epitopes - metabolism; Humans; Major Histocompatibility Complex - immunology; MHC; Microscopy, Atomic Force; Modelling; Models, Molecular; Peptides - immunology; Peptides - metabolism; Pipeline; Protein Binding; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; T cell receptor; T-Cell Antigen Receptor Specificity; T-Lymphocytes - immunology
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2017.12.019

•Identification the TCR cognate target is achieved using force-field based models.•Performance depends on the ability to both accurately predict the binding of the peptide to the MHC and modeling the TCR:p:MHC complex structure.•A modeling pipeline for TCR:p:MHC structure prediction is proposed and evaluated.•Cross-validation experiments confirms model robustness. 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.