Side chain substitution benchmark for peptide/MHC interaction

Abstract

The prediction of T-cell epitopes is an essential part in virtual immunology. Apart from sequence-based techniques, which achieve good results but fail to give insight into the binding behavior of a certain peptide binding to a major histocompatibility complex, structure-based approaches are another important technique. An essential step is the correct placement of the side chains for a given peptide in cases where no experimental data for the structure are available. To our knowledge, no benchmark for side chain substitution in the area of HLA has been reported in the literature. Here, we present a comparison of five different tools (SCWRL, SCATD, SPDBV, SCit, IRECS) applicable for side chain substitution. Each tool is tested on 29 different HLA-A2 structures with experimentally known side chain positions. Parts of the benchmark are correctness, reliability, runtime, and usability. For validation, the root mean square deviations between X-ray structures and predicted structures are used. All tools show different strengths and weaknesses.

Figure 1.

RMSD between predicted and X-ray structure. (A) Box plots of the RMSD values grouped for each tool. (B) Average RMSD values for each amino acid type. (C) RMSD values for each complex. (D) RMSD values for each position. Positions 2 and 9 are anchor residues, while position 6 is an auxiliary anchor.

Figure 2.

Dihedral angles: Chi1 and Chi2 prediction accuracy in percentage over all amino acids under the assumption that a certain threshold between 0° and 180° is chosen. A residue is classified as correct if its angle is below the current threshold. Residues that do not have a Chi1 and/or Chi2 angle are excluded.

Figure 3.

Average runtime over all complexes.

Figure 4.

Workflow of the benchmark.

Figure 5.

Peptides/MHC complex: The β-sheet floors of the binding grooves were superimposed to align the 29 peptides. The α₁ helix of the MHC is hidden to allow direct insight into the binding groove. White indicates MHC α-chain and β₂-microglobulin.