Modeling the interactions of a peptide-major histocompatibility class I ligand with its receptors. I. Recognition by two alpha beta T cell receptors

A three-dimensional model of the complex between an Influenza Hemagglutinin peptide, Ha(255-262), and its restricting element, the mouse major histoco mpatibility complex (MHC) class I molecule, K-k, was built by homology mode ling and subsequently refined by simulated annealing and restrained molecul ar dynamics. Next, three-dimensional models of two different T cell recepto rs (TCRs) both specific for the Ha(255-263)/K-k complex were generated base d on previously published TCR X-ray structures. Finally, guided by the rece ntly published X-ray structures of ternary TCR/peptide/MHC-I complexes, the TCR models were successfully docked into the Ha(255-262)/K-k model. We hav e previously used a systematic and exhaustive panel of 144 single amino aci d substituted analogs to analyze both MHC binding and T cell recognition of the parental viral peptide. This large body of experimental data was used to evaluate the models. They were found to account well for the experimenta lly obtained data, lending considerable support to the proposed models and suggesting a universal docking mode for alpha beta TCRs to MHC-peptide comp lexes. Such models may also be useful in guiding future rational experiment ation.