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Computational Modeling of T Cell Receptor Complexes

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Computational Design of Ligand Binding Proteins

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1414))

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.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN, 46556, USA

    Timothy P. Riley, Nishant K. Singh & Brian M. Baker

  2. Harper Cancer Research Institute, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN, 46556, USA

    Timothy P. Riley, Nishant K. Singh & Brian M. Baker

  3. Institute for Bioscience and Biotechnology Research, University of Maryland, 9600 Gudelsky Drive, Rockville, MD, 20850, USA

    Brian G. Pierce

  4. Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Zhiping Weng

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  1. Timothy P. Riley
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  2. Nishant K. Singh
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  3. Brian G. Pierce
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  4. Zhiping Weng
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  5. Brian M. Baker
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Corresponding author

Correspondence to Brian M. Baker .

Editor information

Editors and Affiliations

  1. Division of Basic Sciences, Fred Hutchinson Cancer Research Cen, Seattle, Washington, USA

    Barry L. Stoddard

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Riley, T.P., Singh, N.K., Pierce, B.G., Weng, Z., Baker, B.M. (2016). Computational Modeling of T Cell Receptor Complexes. In: Stoddard, B. (eds) Computational Design of Ligand Binding Proteins. Methods in Molecular Biology, vol 1414. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3569-7_19

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  • DOI: https://doi.org/10.1007/978-1-4939-3569-7_19

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3567-3

  • Online ISBN: 978-1-4939-3569-7

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