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Computational Design of Ligand Binding Proteins pp 305–318Cite as

Computational Reprogramming of T Cell Antigen Receptor Binding Properties

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

Abstract

T-cell receptor (TCR) binding to peptide/MHC is key to antigen-specific cellular immunity, and there has been considerable interest in modulating TCR affinity and specificity for the development of therapeutics and imaging reagents. While in vitro engineering efforts using molecular evolution have yielded remarkable improvements in TCR affinity, such approaches do not offer structural control and can adversely affect receptor specificity, particularly if the attraction towards the MHC is enhanced independently of the peptide. Here we describe an approach to computational design that begins with structural information and offers the potential for more controlled manipulation of binding properties. Our design process models point mutations in selected regions of the TCR and ranks the resulting change in binding energy. Consideration is given to designing optimized scoring functions tuned to particular TCR-peptide/MHC interfaces. Validation of highly ranked predictions can be used to refine the modeling methodology and scoring functions, improving the design process. Our approach results in a strong correlation between predicted and measured changes in binding energy, as well as good agreement between modeled and experimental structures.

Key words

  • T cell receptor
  • Structure-guided design
  • Rosetta
  • Binding

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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

Authors
  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. Brian M. Baker
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  5. Zhiping Weng
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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., Baker, B.M., Weng, Z. (2016). Computational Reprogramming of T Cell Antigen Receptor Binding Properties. 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_18

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  • DOI: https://doi.org/10.1007/978-1-4939-3569-7_18

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