computer modeling in molecular biology.pdf

7 Major Histocompatibility Complex Class I Protein-Peptide Interactions 185demonstrates that despite the inherent bias towards the HLA-A2 structure of themodel built HLA-Aw68 structure, that it displays RMS deviations of the same orderof magnitude to HLA-A2 as the crystallographic structure. The RMS deviations forthe H-2Kb model in comparison to the two H-2Kb crystallographic structuresdisplay that models of MHC molecules of other loci or species may be built whichare an accurate reflection of the true structure.7.3 The Structure of the Peptide in the GrooveIn order to simulate the complexed state of MHC class I molecule and peptide accuratelywe must fully understand the role played by the peptide, the functionalityof the complex, and the shape of the peptide observed in crystal structures to date.The first comment which may be made about the structure of the peptide bound tothe class I molecule is that it is, in essence, a linear structure. The ~/I,Y torsion anglesof the peptide backbone lie largely within the /?-sheet region of the Ramachandranplot. The ends of the peptide are heavily buried within the MHC molecule and thecentre of the peptide bulges out of the groove. The magnitude of the bulge is apparentlya function of the length of the peptide bound; octamers are essentiallylinear, nonamers have a larger more pronounced bulge at P4 and P5 and presumablydecamers bulge even more.Figures 7-9 and 7-10 show the highly conserved residues which ligate the N- andC-termini of the peptide. The majority of direct hydrogen bonding contacts madeto the MHC molecule from the peptide are made by the termini, with the majorityof contacts within the central bulge of the peptide being mediated by water. In thismanner a certain degree of promiscuity is afforded to the binding of peptide withoutcompromising the structural integrity of the peptide-MHC interaction. If the termini,or residues close to them are the only parts of the epitope which need be conservedbetween peptides, a far greater number of different peptides may be boundthan if there were restrictions both close to the termini and in the centre of the peptide.In a system where the peptide is such an integral part of the folding pathway andstability of the molecule, the structure and the accuracy of simulation of the peptidecomponent are of paramount importance. The ground state of the MHC moleculeis different from the state in which peptide is bound and cannot be accessed bycrystallography. The different structure of the ground state can be directly shown bythe inability of conformationally dependant monoclonal antibodies to recognise differentstates within the folding pathway to those against which they were generated.In order to achieve the “compact” conformation, the class I molecule must bindboth peptide and &microglobulin. However the shape of the molecule before and