MONTE-CARLO STUDY OF THE EFFECT OF BETA(2)-MICROGLOBULIN ON THE BINDING CLEFT OF THE HLA-A2 COMPLEX

Peptide recognition by class I products of the major histocompatibilit y complex requires association of the class I heavy chain with beta(2) -microglobulin. We present results of Monte Carlo simulations of the b eta-pleated sheet floor of the human class I MHC molecule, HLA-A2, wit h and without beta(2)-microglobulin. We find a significant effect of b eta(2)-microglobulin on the side chains of residues near a region that would accommodate the C-terminus of a bound peptide. By modeling simu ltaneously each loop and its neighboring strand at either end of the c lass I cleft, we find that beta(2)-microglobulin restricts the conform ational space of residues that are central to binding peptides. The ef fect is most pronounced for R97 and H114 and somewhat less important f or Y99 and Y116, the latter forming strong hydrogen bonds with neighbo ring residues in the heavy chain itself.