Free energy mapping of class I MHC molecules and structural determination of bound peptides.

Free energy maps of the binding site are constructed for class I major histocompatibility complex (MHC) proteins, by rotating and translating amino acid probes along the cleft, and performing a side-chain conformational search at each position. The free energy maps are used to determine favorable residue positions that are then combined to form docked peptide conformations. Because the generic backbone structural motif of peptides bound to class I MHC is known, the mapping is restricted to appropriate regions of the site, but allows for the sometimes substantial variations in backbone and side-chain conformations. In a test demonstrating the quality of predictions for a known MHC site using only a rotational and conformational search, we started from the crystal structure of the HIV-1 gp120/HLA-A2 complex, and predicted the HLA-A2 bound structures of peptides from the influenza matrix protein, the HIV-1 reverse transcriptase, and the human T cell leukemia virus. The calculated peptides are at 1.6, 1.3, and 1.4 A all-atom RMSDs from their respective crystal structures (Madden DR, Garboczi DN, Wiley DC, 1993). A further test, which also included a local translational search, predicted structures across MHCs. In particular, we obtained the Kb/SEV-9 complex (Fremont DH et al., 1992, Science 257:919-927) starting with the complex between HLA-B27 and a generic peptide (Madden DR, Gorga JC, Strominger JL, Wiley DC, 1991, Nature (Lond) 353:321-325), with an all-atom RMSD of 1.2 A, indicating that the docking procedure is essentially as effective for predictions across MHCs as it is for determinations within the same MHC, although at substantially greater computational cost. The requirements for further improvement in accuracy are identified and discussed briefly.