title: Computational determination of side chain specificity for pockets in class I MHC molecules.
abstract: 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 identify the joint conformations of peptide side chains and side chains comprising the MHC pocket, followed by conformational selection, using a target function, based on solvation energies and modified electrostatic energies. The method was applied to the B pocket region of five MHC molecules, which were chosen to encompass the full range of specificities displayed by anchors at peptide position 2. These were a medium hydrophobic residue (Leu or Met) for HLA-A*0201, a basic residue (Arg or Lys) for HLA-B*2705; a small hydrophobic residue (Val) for HLA-A*6801, an acidic residue (Glu) for HLA-B*4001 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 their 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 computationally.
authors.affiliation: Department of Biomedical Engineering, Boston University, MA 02215, USA.
authors.forename: G
authors.initials: G
authors.lastname: Vasmatzis
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: J L
authors.initials: JL
authors.lastname: Cornette
authors.forename: C
authors.initials: C
authors.lastname: DeLisi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000939:Epitopes / Q000737:chemistry*; D006680:HLA Antigens / Q000737:chemistry*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D008432:Mathematical Computing; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D055672:Static Electricity
chemical_list: D000939:Epitopes; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides