Flexibility of amino acid residues at position four of nonapeptides enhances their binding to human leucocyte antigen (HLA) molecules

The binding affinity of synthetic nonapeptides to human leucocyte antigens (HLA) molecules of the A0201 allotype, the most common in Caucasian, is enh anced or reduced by suitable amino acid substitutions at position 4, as a r esult of increased or decreased chain flexibility. A higher flexibility of the bond at this position correlates with an easier accomodation of the fra gment into the HLA groove, while rigidity of the peptide chain appears to i nterfere. These data are based on two lines of evidence: a) most natural hi gh affnity ligands for HLA-A0201 possess, at position 4, flexible residues b) substitutions of such residues by rigid amino acids results in a decreas e of binding affinity.