PROMINENT ROLE OF SECONDARY ANCHOR RESIDUES IN PEPTIDE BINDING TO HLA-A2.1 MOLECULES

The functional determinants of histocompatibility leukocyte antigen (H LA)-A2.1-peptide interactions have been detailed by the use of quantit ative molecular binding assays and a chemically synthesized library of naturally occurring epitopes. The importance of hydrophobic anchor re sidues in position 2 and the C-terminus minus was confirmed. These anc hors are necessary, but not sufficient, for high affinity binding, as the predictions based solely on these anchors are only about 30% accur ate. Prominent roles for several other positions (1, 3, and 7) were al so demonstrated. The location of these residues within the peptides ma tches secondary A2.1 pockets previously demonstrated by X-ray crystall ography. From a functional standpoint, similar dominant negative effec ts on binding were observed for charged residues in both nonamers and decamers, while positive effects differed between nonamers and decamer s. An extended motif taking into account secondary anchors increased t he predictability of A2.1-binding epitopes to a level of 70%, undersco ring the practical usefulness of extended motifs.