MHC–Peptide Binding is Assisted by Bound Water Molecules

Water plays an important role in determining the high affinity of epitopes to the class I MHC complex. To study the energy and dynamics of water interactions in the complex we performed molecular dynamics simulation of the class I MHC–HLA2 complex bound to the HIV reverse transcriptase epitope, ILKEPVHGV, and in the absence of the epitope. Each simulation was extended for 5 ns. We studied the processes of water penetration in the interface between MHC and peptide, and identified 14 water molecules that stay bound for periods longer than 1 ns in regions previously identified by crystallography. These water molecules in the interface perform definite “tasks” contributing to the binding energy: hydrogen bond bridges between MHC and peptide and filling empty spaces in the groove which enhance affinity without contributing to epitope specificity. We calculate the binding energy for interfacial water molecules and find that there is an overall gain in free energy resulting from the formation of water clusters at the epitope–MHC interface. Water molecules serving the task of filling empty spaces bind at the interface with a net gain in entropy, relative to their entropy in bulk. We conclude that water molecules at the interface play the role of active mediators in the MHC–peptide interaction, and might be responsible for the large binding affinity of the MHC complex to a large number of epitope sequences.