Automatic sequence design of MHC Class-I binding peptides impairing CD8+ T cell recognition

Koji Ogata — 2008-04-22T10:50:59-00:00

J. Biol. Chem. (30 October 2002), M206853200.

An automatic protein design procedure is used to compute amino acid sequences of peptides likely to bind the HLA-A2 MHC class-I allele. The only information used by the procedure are a structural template, a rotamer library, and a well-established classical empirical force field. The calculations are performed on 6 different templates from x-ray structures of HLA-A0201-peptide complexes. Each template consists of the bound peptide backbone and the full atomic coordinates of the MHC protein. Sequences within 2 kcal/mol of the minimum energy sequence are computed for each template and the sequences from all he templates are combined and ranked by their energies. The 5 lowest energy peptide sequences and 5 other low energy sequences re-ranked on the basis of their similarity to peptides known to bind the same MHC allele, are chemically synthesised and tested for their ability to bind and form stable complexes with the HLA-A2 molecule. The most efficient binders are also tested for inhibition of the T-cell receptor (TCR) recognition of two known CD8+ T effectors. Results show that all 10 peptides bind the expected MHC protein. The 6 strongest binders also form stable HLA-A2-peptide complexes, albeit to varying degrees, and 3 peptides display significant inhibition of CD8+ T cell recognition. These results are rationalised in light of our knowledge of the 3D structures of the HLA-A2-peptide and HLA-A2-peptide-TCR complexes. 10.1074/jbc.M206853200

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Automatic sequence design of MHC Class-I binding peptides impairing CD8+ T cell recognition