Fig. 2.

Consequences of avoiding negative selection on the composition of peptide contact residues of selected TCRs. (A) Schematic description of frustration due to negative selection. The thickness of the bars (or color of peptide amino acids: strong, red; moderate, yellow; weak, blue; very weak, green) is proportional to the interaction energy between TCR and pMHC residues. When developing in a thymus with only one type of endogenous peptide, a TCR that results in a few strong interactions and several weak or moderate interactions with this peptide can survive selection. This is because the total interaction energy falls between the positive- and negative-selection thresholds. The sequence of TCR peptide contact residues shown, that survives selection against one type of peptide in the thymus, would likely be negatively selected when there are many types of peptides in the thymus. For example, a peptide that differs by one amino acid from the first one (shown as a change from E to C) may lead to an additional moderate interaction energy that is sufficient to increase the total interaction energy past the negative selection threshold. (B and C) Selection against many types of peptides in the thymus results in selected TCRs with peptide contact residues with an enhanced frequency of amino acids that interact weakly with all other amino acids. The ordinate is the ratio of the frequencies of occurrence of an amino acid in the peptide contact residues of selected TCRs to preselection TCRs. (B) For the computational results, the abscissa is a list of amino acids ordered according to the maximum energy (as per the MJ interaction potential) with which it interacts with all other amino acids. The qualitative results are robust to changes in potential (Fig. S1 B, D, and F). (C) The ordinate was obtained by analyzing the 18 available crystal structures of TCR-pMHC (I) complexes as described in the text. Amino acids were classified as strongly interacting (IVYWREL) or weakly interacting (QSNTAG) following ref. 23.