Fig. 2: TCR binding to the neoantigen induces a large conformational change in the peptide that leads to new peptide-HLA interactions.

a Illustration of the peptide conformational change that occurs upon the binding of TCR3 and TCR4 to the neoantigen/HLA-A3 complex. The tryptophan at position 6 has flipped from aligning against the α1 helix to nestling between the peptide backbone and the α2 helix (see also Supplementary Fig. 1). b Distribution of conformational changes that occur in nonameric class I MHC complexes upon TCR binding as measured by bound vs. free RMSDs for Cα atoms and all peptide atoms. The RMSD values for the neoantigen upon recognition by TCR3 or TCR4 are shown as orange and yellow stars, respectively. The white squares in the box plots give the average, the gold boxes the interquartile ranges (IQR), lines in the gold boxes the medians, and the whiskers 1.5 × IQR. Although the changes for the backbone are only slightly above the mean, when considering all peptide atoms, the conformational change in the neoantigen is among the largest seen upon TCR recognition of nonamers. Data are from structural analysis of available PDB structures as described in the Methods. c In the TCR4 complex, the pTrp6 side chain is not contacted by the TCR. The indole nitrogen of the flipped conformation of pTrp6 forms a NH-π hydrogen bond with Trp147 of the HLA-A3 α2 helix. d In the complex with TCR3, the pTrp6 side chain is also not contacted by the TCR. The slight repositioning of the pTrp6 side chain in the complex with TCR3 distorts the interaction of pTrp6 with Trp147, although a structural water in close proximity bridges pTrp6 to Asp77 of the α1 helix.