Abstract
The interaction between the class I major histocompatibility complex (MHC), the peptide presented by the MHC and the T-cell receptor (TCR) is a key determinant of the cellular immune response. Here, we present TCRpMHCmodels, a method for accurate structural modelling of the TCR-peptide-MHC (TCR-pMHC) complex. This TCR-pMHC modelling pipeline takes as input the amino acid sequence and generates models of the TCR-pMHC complex, with a median Cα RMSD of 2.31 Å. TCRpMHCmodels significantly outperforms TCRFlexDock, a specialised method for docking pMHC and TCR structures. TCRpMHCmodels is simple to use and the modelling pipeline takes, on average, only two minutes. Thanks to its ease of use and high modelling accuracy, we expect TCRpMHCmodels to provide insights into the underlying mechanisms of TCR and pMHC interactions and aid in the development of advanced T-cell-based immunotherapies and rational design of vaccines. The TCRpMHCmodels tool is available at http://www.cbs.dtu.dk/services/TCRpMHCmodels/.
Highlights
As part of the adaptive immune response, T-cells recognise and kill pathogenic or pathogen-infected cells[1,2]
While tools to deal with peptide-MHC binding and predicting T-cell epitopes have been developed over the last decade[14,15,16,17], limited work has been dedicated to the task of generating accurate T-cell receptors (TCRs)-presented by major histocompatibility complexes (pMHCs) models
We believe that the models produced by our tool in combination with refined binding energies can be used to provide valuable insights into the mechanisms underlying the interaction between TCRs and pMHCs, and that the models can guide the refined prediction of T-cell epitopes
Summary
As part of the adaptive immune response, T-cells recognise and kill pathogenic or pathogen-infected cells[1,2]. We focus on modelling the TCR-pMHC complex of αβ-TCRs and MHC class I molecules, as these constitute the majority of the available structural complexes. Numerous sequence- and structure-based tools have been developed to predict and model the structure of and/or the interaction between the peptide and the MHC class I molecule[21,22,23,24,25,26,27]. While tools to deal with peptide-MHC binding and predicting T-cell epitopes have been developed over the last decade[14,15,16,17], limited work has been dedicated to the task of generating accurate TCR-pMHC models. We believe that the models produced by our tool in combination with refined binding energies can be used to provide valuable insights into the mechanisms underlying the interaction between TCRs and pMHCs, and that the models can guide the refined prediction of T-cell epitopes
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