ATLAS: A database linking binding affinities with structures for wild-type and mutant TCR-pMHC complexes

Abstract

The ATLAS (Altered TCR Ligand Affinities and Structures) database (https://zlab.umassmed.edu/atlas/web/) is a manually curated repository containing the binding affinities for wild-type and mutant T cell receptors (TCRs) and their antigens, peptides presented by the major histocompatibility complex (pMHC). The database links experimentally measured binding affinities with the corresponding three dimensional (3D) structures for TCR-pMHC complexes. The user can browse and search affinities, structures, and experimental details for TCRs, peptides, and MHCs of interest. We expect this database to facilitate the development of next-generation protein design algorithms targeting TCR-pMHC interactions. ATLAS can be easily parsed using modeling software that builds protein structures for training and testing. As an example, we provide structural models for all mutant TCRs in ATLAS, built using the Rosetta program. Utilizing these structures, we report a correlation of 0.63 between experimentally measured changes in binding energies and our predicted changes. Proteins 2017; 85:908-916. © 2016 Wiley Periodicals, Inc.

Keywords: 3D viewer; Rosetta; adaptive immunity; binding energy; protein modeling; scoring functions.

Fig. 1

ATLAS data statistics. (a) A6/Tax/HLA-A*02:01 TCR-pMHC complex (PDB: 1AO7). TCR α and β chains (green, orange), MHC molecule (cyan), peptide (magenta), and β₂ microglobulin (yellow) are shown in cartoon style. (b) Histogram of the binding affinities of TCR-pMHC complexes in ATLAS. (c) Pie charts for percentage of entries with modeled mutations made to the TCR, the MHC or the peptide (left), percentage of MHC subclasses (right).

Fig. 2

Results of predicting binding free energies in ATLAS. (a) Table of coefficients and p-values for all energy features of the regression analysis. One insignificant feature (repulsive van der Waals) is highlighted in red. (b) Scatterplot of predicted ΔG versus ΔG determined by SPR for all ATLAS entries. Linear regression analysis was performed to predict ΔG using the following features: attractive van der Waals energy, Lazaridis-Karplus solvation energy and all four hydrogen bond energy terms. r = 0.48 and RMSE = 1.48 kcal/mol. (c) Scatterplot of predicted ΔΔG versus ΔΔG determined by SPR for 575 mutant ATLAS entries determined by regression analysis using the following features: attractive van der Waals energy, Lazaridis-Karplus solvation energy and sidechain-sidechain hydrogen bond energy. r = 0.63 and RMSE = 1.58 kcal/mol. Red line represents perfect prediction.

Fig. 3

ATLAS web interface and data accession. (a) The search page for querying the ATLAS database. ATLAS is searchable by TCR (1) and MHC (2) features, binding energies ΔG below a user specified kcal/mol (3) and by case-insensitive peptide sequence motifs (4). (b) The search results page linking binding energies to complex structures. The PDB structure specified in (1) refers to a structure identical to the TCR-pMHC used in the binding assay. The template PDB structure in (2) can be designed to replicate the TCR-pMHC used in the binding assay by modeling the mutations listed in the TCR mutation, MHC mutation, and Peptide mutation columns. (c) Protein Viewer and individual PDB downloads. An example shows the selection of PDB ID 1AO7 from the Template PDB column for the D26W TCR mutant. Template structures and Rosetta designed structures are both available for download.