International Immunology, Vol. 12, No. 7, 949-957,
July 2000
© 2000 Japanese Society for Immunology
Water dynamics at the binding interface of four different HLA-A2–peptide complexes
Department of Pharmaceutical Sciences, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, USA
Correspondence to: I. S. Haworth
Because only a limited number of MHC molecules are available for presentation of a large number of peptides, each of these MHC molecules must be able to bind promiscuously many different peptides at an affinity sufficient for stable presentation. Here we show, for the MHC molecule HLA-A2, that this ability may be facilitated by a flexible water network that forms an interface between the MHC molecule and the peptide. Using the SURFNET program we have computed the `gaps' present in the peptide-binding groove in the X-ray structures of complexes of HLA-A2 with four different bound peptides. The volume of these gaps increases with increasing peptide hydrophilicity. Using molecular dynamics simulations, we show that the water molecules in the binding groove of complexes of HLA-A2 with the more hydrophilic peptides are largely disordered, but a number of defined water-binding sites are also discernable. Conversely, for complexes of HLA-A2 with the more hydrophobic peptides, the water molecules are more rigidly bound at the MHC–peptide interface and a number of well-defined water-binding sites exist. However, even these well-defined sites may not be permanently occupied by the same water molecule and in the dynamics calculations we observed exchange of water molecules between such sites.
Keywords: MHC, molecular dynamics, peptide, water mediated
1 Present address: Department of Surgery, Division of Surgical Oncology, University of California at Los Angeles, 10833 LeConte Avenue, Los Angeles, CA 90095, USA
2 Present address: Department of Medicine, BMT B11, University of Southern California, Los Angeles, CA 90033, USA
Transmitting editor: T. Sasazuki
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