PERIODIC VARIATION IN SIDE-CHAIN POLARITIES OF T-CELL ANTIGENIC PEPTIDES CORRELATES WITH THEIR STRUCTURE AND ACTIVITY

We present an analysis that synthesizes information on the sequence, s tructure, and motifs of antigenic peptides, which previously appeared to be in conflict, Fourier analysis of T-cell antigenic peptides indic ates a periodic variation in amino acid polarities of 3-3.6 residues p er period, suggesting an amphipathic alpha-helical structure, However, the diffraction patterns of major histocompatibility complex (MHC) mo lecules indicate that their ligands are in an extended non-alpha-helic al conformation, We present two mutually consistent structural explana tions for the source of the alpha-helical periodicity, based on an obs ervation that the side chains of MHC-bound peptides generally partitio n with hydrophobic (hydrophilic) side chains pointing into (out of) th e cleft, First, an analysis of haplotype-dependent peptide motifs indi cates that the locations of their defining residues tend to force a pe riod 3-4 variation in hydrophobicity along the peptide sequence, in a manner consistent with the spacing of pockets in the MHC. Second, rece nt crystallographic determination of the structure of a peptide bound to a class II MHC molecule reveals an extended but regularly twisted p eptide with a rotation angle of about 130 degrees, We show that simila r structures with rotation angles of 100-130 degrees are energetically acceptable and also span the Length of the MHC cleft. These results p rovide a sound physical chemical and structural basis for the existenc e of a haplotype-independent antigenic motif which can be particularly important in limiting the search time for antigenic peptides.