Computational Reprogramming of T Cell Antigen Receptor Binding Properties

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


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 



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
  • Brian M. Baker
    • 1
    • 2
  • Zhiping Weng
    • 4
  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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