U. Sezerman et al., FREE-ENERGY MAPPING OF CLASS-I MHC MOLECULES AND STRUCTURAL DETERMINATION OF BOUND PEPTIDES, Protein science, 5(7), 1996, pp. 1272-1281
Free energy maps of the binding site are constructed for class I major
histacompatibility complex (MHC) proteins, by rotating and translatin
g amino acid probes along the cleft, and performing aside-chain confor
mational search at each position. The free energy maps are used to det
ermine favorable residue positions that are then combined to form dock
ed peptide conformations. Because the generic backbone structural moti
f of peptides bound to class I MHC is known, the mapping is restricted
to appropriate regions of the site, but allows for the sometimes subs
tantial variations in backbone and side-chain conformations. In a test
demonstrating the quality of predictions for a known MHC site using o
nly a rotational and conformational search, we started from the crysta
l structure of the HIV-1 gp120/HLA-A2 complex, and predicted the HLA-A
2 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 Angstrom all-atom RMSDs f
rom 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 t
he K-b/SEV-9 complex (Fremont DH et al., 1992, Science 257:919-927) st
arting 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 Angstrom, indicating that the docking
procedure is essentially as effective for predictions across MHCs as i
t 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.