Water dynamics at the binding interface of four different HLA-A2-peptide complexes

Because only a limited number of MHC molecules are available for presentati on 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-AP, that this ability may be facilitated by a flexible water network that forms an interf ace 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-AZ with four different bound peptides, The volume of these gaps increases with increasing peptide hydrophilicity, Usin g molecular dynamics simulations, we show that the water molecules in the b inding groove of complexes of HLA-AS with the more hydrophilic peptides are largely disordered, but a number of defined water-binding sites are also d iscernable. Conversely, for complexes of HLA-AP with the more hydrophobic p eptides, the water molecules are more rigidly bound at the MHC-peptide inte rface 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 mo lecules between such sites.