Automatic sequence design of major histocompatibility complex class I binding peptides impairing CD8+ T cell recognition.
An automatic protein design procedure was used to compute amino acid sequences of peptides likely to bind the HLA-A2 major histocompatibility complex (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 six 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 the templates are combined and ranked by their energies. The five lowest energy peptide sequences and five other low energy sequences re-ranked on the basis of their similarity to peptides known to bind the same MHC allele are chemically synthesized 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 recognition of two known CD8(+) T effectors. Results show that all 10 peptides bind the expected MHC protein. The six strongest binders also form stable HLA-A2-peptide complexes, albeit to varying degrees, and three peptides display significant inhibition of CD8(+) T cell recognition. These results are rationalized in light of our knowledge of the three-dimensional structures of the HLA-A2-peptide and HLA-A2-peptide-T cell receptor complexes.
Ogata
Koji
K
Service de Conformation de Macromolécules Biologiques et Bioinformatique, CP263, Centre de Biologie Structurale et Bioinformatique, Université Libre de Bruxelles, Blvd. du Triomphe, Belgium.
Jaramillo
Alfonso
A
Cohen
William
W
Briand
Jean-Paul
JP
Connan
Francine
F
Choppin
Jeannine
J
Muller
Sylviane
S
Wodak
Shoshana J
SJ
D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
D015789:HLA-A2 Antigen; D010455:Peptides