Monte Carlo study of the effect of β₂‐microglobulin on the binding cleft of the HLA‐A2 complex

Abstract

Peptide recognition by class I products of the major histocompatibility complex requires association of the class I heavy chain with /32-microglobulin. We present results of Monte Carlo simulations of the @-pleated sheet floor of the human class I MHC molecule, HLA-A2, with and without P,-microglobulin. We find a significant effect of &microglobulin on the side chains of residues near a region that would accommodate the C-terminus of a bound peptide. By modeling simultaneously each loop and its neighboring strand at either end of the class I cleft, we find that P2-microglobulin restricts the conformational space of residues that are central to binding peptides. The effect is most pronounced for R97 and H114 and somewhat less important for Y99 and Y116, the latter forming strong hydrogen bonds with neighboring residues in the heavy chain itself.