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

ABSTRACT: 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.

SUBMITTER: Pierce BG

PROVIDER: S-EPMC3575858 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Pierce Brian G BG Weng Zhiping Z

Protein science : a publication of the Protein Society 20130101 1

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 ...[more]

PMID: 23109003

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Project description:BACKGROUND:MHC class II proteins bind oligopeptide fragments derived from proteolysis of pathogen antigens, presenting them at the cell surface for recognition by CD4+ T cells. Human MHC class II alleles are grouped into three loci: HLA-DP, HLA-DQ and HLA-DR. In contrast to HLA-DR and HLA-DQ, HLA-DP proteins have not been studied extensively, as they have been viewed as less important in immune responses than DRs and DQs. However, it is now known that HLA-DP alleles are associated with many autoimmune diseases. Quite recently, the X-ray structure of the HLA-DP2 molecule (DPA*0103, DPB1*0201) in complex with a self-peptide derived from the HLA-DR ?-chain has been determined. In the present study, we applied a validated molecular docking protocol to a library of 247 modelled peptide-DP2 complexes, seeking to assess the contribution made by each of the 20 naturally occurred amino acids at each of the nine binding core peptide positions and the four flanking residues (two on both sides). RESULTS:The free binding energies (FBEs) derived from the docking experiments were normalized on a position-dependent (npp) and on an overall basis (nap), and two docking score-based quantitative matrices (DS-QMs) were derived: QMnpp and QMnap. They reveal the amino acid preferences at each of the 13 positions considered in the study. Apart from the leading role of anchor positions p1 and p6, the binding to HLA-DP2 depends on the preferences at p2. No effect of the flanking residues was found on the peptide binding predictions to DP2, although all four of them show strong preferences for particular amino acids. The predictive ability of the DS-QMs was tested using a set of 457 known binders to HLA-DP2, originating from 24 proteins. The sensitivities of the predictions at five different thresholds (5%, 10%, 15%, 20% and 25%) were calculated and compared to the predictions made by the NetMHCII and IEDB servers. Analysis of the DS-QMs indicated an improvement in performance. Additionally, DS-QMs identified the binding cores of several known DP2 binders. CONCLUSIONS:The molecular docking protocol, as applied to a combinatorial library of peptides, models the peptide-HLA-DP2 protein interaction effectively, generating reliable predictions in a quantitative assessment. The method is structure-based and does not require extensive experimental sequence-based data. Thus, it is universal and can be applied to model any peptide - protein interaction.

Project description:BackgroundT cell receptor (TCR) molecules are involved in the adaptive immune response as they distinguish between self- and foreign-peptides, presented in major histocompatibility complex molecules (pMHC). Former studies showed that the association angles of the TCR variable domains (Vα/Vβ) can differ significantly and change upon binding to the pMHC complex. These changes can be described as a rotation of the domains around a general Center of Rotation, characterized by the interaction of two highly conserved glutamine residues.MethodsWe developed a computational method, DynaDom, for the prediction of TCR Vα/Vβ inter-domain and TCR/pMHC orientations in TCRpMHC complexes, which allows predicting the orientation of multiple protein-domains. In addition, we implemented a new approach to predict the correct orientation of the carboxamide endgroups in glutamine and asparagine residues, which can also be used as an external, independent tool.ResultsThe approach was evaluated for the remodeling of 75 and 53 experimental structures of TCR and TCRpMHC (class I) complexes, respectively. We show that the DynaDom method predicts the correct orientation of the TCR Vα/Vβ angles in 96 and 89% of the cases, for the poses with the best RMSD and best interaction energy, respectively. For the concurrent prediction of the TCR Vα/Vβ and pMHC orientations, the respective rates reached 74 and 72%. Through an exhaustive analysis, we could show that the pMHC placement can be further improved by a straightforward, yet very time intensive extension of the current approach.ConclusionsThe results obtained in the present remodeling study prove the suitability of our approach for interdomain-angle optimization. In addition, the high prediction rate obtained specifically for the energetically highest ranked poses further demonstrates that our method is a powerful candidate for blind prediction. Therefore it should be well suited as part of any accurate atomistic modeling pipeline for TCRpMHC complexes and potentially other large molecular assemblies.

Dataset Information

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

Publications

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

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