computer modeling in molecular biology.pdf

7 Major Histocompatibility Complex Class I Protein-Peptide Interactions 181subtle but distinct conformational changes. In a system such as the MHC whererecognition by a third body, the T-cell receptor is required to give the system a functionality,a change in the structure of the MHC molecule may remove the responseof the T-cell or may indeed cause an aberrant response, therefore it is a sign of thehighly adaptive nature of the MHC molecule that this sort of allogenic reaction appearsnot to be the norm.This high similarity of the class I molecule between alleles and between structuresof an individual allele works both for and against those who wish to model andsimulate these structures. The high similarity of the crystal structures aids the initialbuilding and optimisation of the structure. Many knowledge based modelling programstake note of the orientation of the Ca to Cj3, and Cp to Cy bonds, where appropriate,for building the side chain geometries of non-homologous residues. It canbe observed from an overlay of the residues involved in the region surrounding theB-pocket of HLA-A2 and HLA-Aw68 and HLA-B27 that one structure may be accuratelymodelled from another (see Figures 7-6 and 7-7). Indeed the analysis of themodel for HLA-Aw68 built from the structures of HLA-A2 and HLA-B27demonstrates the fit of the model structure to its crystallographic counterpart(Figure 7-8). The analysis of RMS deviations between HLA-A2 and HLA-Aw68Figure 7-6. Comparison of residues in the region surrounding the “45” or B-pocket in theHLA-A2 (3hla:- pale-grey) and HLA-Aw68 (2hla:- dark-grey) structures. It can be readilyobserved from this view that several of the residues can be found in identical or near identicalorientations. This facilitates modelling of as yet un-crystallised alleles with a high degree ofcertainty into the accuracy of the outcome. It can be observed in both this view and the companionview (Figure 7-7) that an endo-ex0 flip has occurred in the proline geometry at position50.