COMPUTATIONAL DETERMINATION OF SIDE-CHAIN SPECIFICITY FOR POCKETS IN CLASS-I MHC MOLECULES

We show that a rapidly executable computational procedure provides the basis for a predictive understanding of antigenic peptide side chain specificity, for binding to class I major histocompatibility complex ( MHC) molecules. The procedure consists of a combined search to identif y the joint conformations of peptide side chains and side chains compr ising the MHC pocket, followed by conformational selection, using a ta rget function, based on solvation energies and modified electrostatic energies. The method was applied to the B pocket region of five MHC mo lecules, which were chosen to encompass the full range of specificitie s displayed by anchors at peptide position 2. These were a medium hydr ophobic residue (Leu or Met) for HLA-A0201, a basic residue (Arg or L ys) for HLA-B2705; a small hydrophobic residue (Val) for HLA-A*6801, an acidic residue (Glu) for HLA-B4001 and a bulky residue (Tyr) for H -2K(d). The observed anchors are correctly predicted in each case. The agreement for HLA-B40 and H-2K(d) is especially promising, since thei r structures have not yet been determined experimentally. Because the experimental determination of motifs by elution is difficult and these calculations take only hours on a high speed workstation, the results open the possibility of routine determination of motifs computational ly. (C) 1997 Elsevier Science Ltd.