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Computational Design of Ligand Binding Proteins

Volume 1414 of the series Methods in Molecular Biology pp 319-340

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Computational Modeling of T Cell Receptor Complexes

  • Timothy P. RileyAffiliated withDepartment of Chemistry and Biochemistry, University of Notre DameHarper Cancer Research Institute, University of Notre Dame
  • , Nishant K. SinghAffiliated withDepartment of Chemistry and Biochemistry, University of Notre DameHarper Cancer Research Institute, University of Notre Dame
  • , Brian G. PierceAffiliated withInstitute for Bioscience and Biotechnology Research, University of Maryland
  • , Zhiping WengAffiliated withProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School
  • , Brian M. BakerAffiliated withDepartment of Chemistry and Biochemistry, University of Notre DameHarper Cancer Research Institute, University of Notre Dame Email author 

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Abstract

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