computer modeling in molecular biology.pdf

7 Major Histocompatibility Complex Class I Protein-Peptide Interactions 181Figure 7-10. View of the C-terminal binding ligands in HLA-B*2705. In the structures ofHLA-B*2705 and HLA-A*6801 Thr80 interacts indirectly with the C-terminus of the peptidevia a water molecule and ?frr123 interacts with ?frr84. In some HLA-B locus alleles where position80 is the subject of a non-conservative threonine to leucine substitution the distributionof water molecules appears from molecular dynamics studies to be perturbed (see Section7.8). In some mouse and human non-classical or medial class I MHC molecules there aresubstitutions for positions 143 and 147 that would appear to disturb this network considerably.the spacing between two discrete residues statistically enhances the probability offinding an epitope within a sequence.The structure of HLA-Aw68 with a collection of endogenous peptides at 1.9 Aclearly demonstrates that the termini of the peptide are highly similar in peptides ofdissimilar length. In this structure clear interpretable density is present for positionsPl-P3 and PC-1 to PC but in the central bulge of the peptide the lack of contiguouselectron density suggests that in the region of the peptide between the anchors severalconformations occur. This finding is in agreement with observations which may bemade from an overlay of the octamer and nonamer peptide structures bound to theH-2Kb molecule. For these peptides the backbones for positions P1 to P3 and PC-1to PC are virtually identical. The peptides are also co-incident at the PC-3 positionwhich is an anchor in the H-2Kb motif. Thus the only differences between the octamerand nonamer peptide is the shape of the bulge which joins P3 to PC-3. In theoctamer peptide this region is simply more extended than in the nonamer peptide asmight have been expected from the difference in length of the peptide.