Computational Modeling of T Cell Receptor Complexes

  • Timothy P. Riley
  • Nishant K. Singh
  • Brian G. Pierce
  • Zhiping Weng
  • Brian M. Baker
Part of the Methods in Molecular Biology book series (MIMB, volume 1414)


T-cell receptor (TCR) binding to peptide/MHC determines specificity and initiates signaling in antigen-specific cellular immune responses. Structures of TCR–pMHC complexes have provided enormous insight to cellular immune functions, permitted a rational understanding of processes such as pathogen escape, and led to the development of novel approaches for the design of vaccines and other therapeutics. As production, crystallization, and structure determination of TCR–pMHC complexes can be challenging, there is considerable interest in modeling new complexes. Here we describe a rapid approach to TCR–pMHC modeling that takes advantage of structural features conserved in known complexes, such as the restricted TCR binding site and the generally conserved diagonal docking mode. The approach relies on the powerful Rosetta suite and is implemented using the PyRosetta scripting environment. We show how the approach can recapitulate changes in TCR binding angles and other structural details, and highlight areas where careful evaluation of parameters is needed and alternative choices might be made. As TCRs are highly sensitive to subtle structural perturbations, there is room for improvement. Our method nonetheless generates high-quality models that can be foundational for structure-based hypotheses regarding TCR recognition.

Key words

T cell receptor Peptide/MHC Structure Rosetta Loop modeling Docking 



Computational structural immunology in the authors’ laboratories is supported by NIH grants R01GM103773 and R01GM067079 and an award from the Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut. TPR is supported by a fellowship from the Indiana CTSI, funded in part by NIH grant UL1TR001108.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Timothy P. Riley
    • 1
    • 2
  • Nishant K. Singh
    • 1
    • 2
  • Brian G. Pierce
    • 3
  • Zhiping Weng
    • 4
  • Brian M. Baker
    • 1
    • 2
  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre DameUSA
  2. 2.Harper Cancer Research InstituteUniversity of Notre DameNotre DameUSA
  3. 3.Institute for Bioscience and Biotechnology ResearchUniversity of MarylandRockvilleUSA
  4. 4.Program in Bioinformatics and Integrative BiologyUniversity of Massachusetts Medical SchoolWorcesterUSA

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