A flexible docking approach for prediction of T cell receptor-peptide-MHC complexes

Protein Sci. 2013 Jan;22(1):35-46. doi: 10.1002/pro.2181.


T cell receptors (TCRs) are immune proteins that specifically bind to antigenic molecules, which are often foreign peptides presented by major histocompatibility complex proteins (pMHCs), playing a key role in the cellular immune response. To advance our understanding and modeling of this dynamic immunological event, we assembled a protein-protein docking benchmark consisting of 20 structures of crystallized TCR/pMHC complexes for which unbound structures exist for both TCR and pMHC. We used our benchmark to compare predictive performance using several flexible and rigid backbone TCR/pMHC docking protocols. Our flexible TCR docking algorithm, TCRFlexDock, improved predictive success over the fixed backbone protocol, leading to near-native predictions for 80% of the TCR/pMHC cases among the top 10 models, and 100% of the cases in the top 30 models. We then applied TCRFlexDock to predict the two distinct docking modes recently described for a single TCR bound to two different antigens, and tested several protein modeling scoring functions for prediction of TCR/pMHC binding affinities. This algorithm and benchmark should enable future efforts to predict, and design of uncharacterized TCR/pMHC complexes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Histocompatibility Antigens / chemistry*
  • Histocompatibility Antigens / immunology
  • Histocompatibility Antigens / metabolism*
  • Models, Molecular
  • Peptides / chemistry*
  • Peptides / immunology
  • Peptides / metabolism*
  • Protein Binding
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism*


  • Histocompatibility Antigens
  • Peptides
  • Receptors, Antigen, T-Cell