Get access

Structural prediction of peptides binding to MHC class I molecules

Authors

  • Huynh-Hoa Bui,

    1. Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California
    Current affiliation:
    1. La Jolla Institute for Allergy and Immunology, San Diego, California
    Search for more papers by this author
  • Alexandra J. Schiewe,

    1. Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California
    Search for more papers by this author
  • Hermann von Grafenstein,

    1. Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California
    Current affiliation:
    1. Departments of Medicinal and Biological Chemistry and Pharmacology, College of Pharmacy, University of Toledo, Toledo, Ohio
    Search for more papers by this author
  • Ian S. Haworth

    Corresponding author
    1. Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California
    • Department of Pharmaceutical Sciences, University of Southern California, 1985 Zonal Avenue, PSC 304B, Los Angeles, CA 90089
    Search for more papers by this author

Abstract

Peptide binding to class I major histocompatibility complex (MHCI) molecules is a key step in the immune response and the structural details of this interaction are of importance in the design of peptide vaccines. Algorithms based on primary sequence have had success in predicting potential antigenic peptides for MHCI, but such algorithms have limited accuracy and provide no structural information. Here, we present an algorithm, PePSSI (peptide-MHC prediction of structure through solvated interfaces), for the prediction of peptide structure when bound to the MHCI molecule, HLA-A2. The algorithm combines sampling of peptide backbone conformations and flexible movement of MHC side chains and is unique among other prediction algorithms in its incorporation of explicit water molecules at the peptide-MHC interface. In an initial test of the algorithm, PePSSI was used to predict the conformation of eight peptides bound to HLA-A2, for which X-ray data are available. Comparison of the predicted and X-ray conformations of these peptides gave RMSD values between 1.301 and 2.475 Å. Binding conformations of 266 peptides with known binding affinities for HLA-A2 were then predicted using PePSSI. Structural analyses of these peptide-HLA-A2 conformations showed that peptide binding affinity is positively correlated with the number of peptide-MHC contacts and negatively correlated with the number of interfacial water molecules. These results are consistent with the relatively hydrophobic binding nature of the HLA-A2 peptide binding interface. In summary, PePSSI is capable of rapid and accurate prediction of peptide-MHC binding conformations, which may in turn allow estimation of MHCI-peptide binding affinity. Proteins 2006. © 2006 Wiley-Liss, Inc.

Ancillary