computer modeling in molecular biology.pdf

7 Major Histocompatibility Complex Class I Protein-Peptide Interactions 207slightly different manner to those in the HLA-B*2705 dynamics. In the HLA-B*2705model TIP453 moves to fill the space left by the shorter hydrophobic side chain ofthe EBNA 3C peptide. In the HLA-B*2702 model this does not occur as TIP453 istightly bound throughout the trajectory by Asn77, the main chain carbonyl ofThr73, the main chain amide of Leu-P9 and the side chain of GluP8. GluP8 appearsto spend the majority of the dynamics simulation in an orientation which is approximatelyequidistant between the C1 and C2 conformers observed in the HLA-B*2705simulation (see Figure 7-17 d). This conformation is itself stabilised by the movementof TIP451 from its starting position, where in HLA-B*2705 it made hydrogen bondswith the side chains of Asp77, Thr80 and GluP8, to a new position where the sidechains of both GluP8 and Arg83 can be complexed. This movement occurs duringthe first 10 ps of the simulation and is stable for the final 20 ps of the simulation.In the period between 10 ps and 25 ps TIP451 is exchanging between its final orientationand that observed in the HLA-B*2705 crystal structure. TIP451 remains largelyin the position observed in the crystallographic co-ordinates, but has a minor secondaryconformation where, like the pyrrole amine of Trp147, it is chelated by the mainchain carbonyl of P8.In addition to the above simulations another molecular dynamics trajectory wascalculated to determine the extent of the movement available to the arginine sidechain in the P2 binding pocket. The P2 binding pocket of HLA-B27 displays a highlyspecific hydrogen bonding network, and presumably this specificity maintains arigidity of side chain orientation. The experiment was performed fixing all MHCatoms and allowing movement only in the side chain atoms of ArgP2, and the mainchain atoms of ArgP2, the C=O and Ca of P1 and the N-H and Ca of P3. Thislead to a picture of the dynamics of the arginine side chain within the confines ofthe well defined pocket. As can be observed in Figure 7-18 the arginine side chainhas very little movement inside the pocket. The movement is also usually cooperativewith movements performed by the water molecule although which movement iscause and which is effect is impossible to determine. The slight movements ofTIP456 can be compared to those exhibited by TIP461 and the “bulk” solvents ofthe cleft. TIP461 has virtually no movement throughout the dynamics trajectory andthe hydrogen bonds between TIP461, Glu45, Glu63 and Tyrl71 are stable throughoutthe trajectory. Amongst the “bulk” solvent around the P2 pocket markedly greatermovement is observed and at several points in the dynamics trajectory movementstowards the exchange of solvent positions are observed. In Figure 7-18 the hydrogenbonding patterns which are shown are for the starting conformation of the complex.The molecular dynamics calculations carried out on the complexes of the EBNA3C peptide and HLA-B*2702 and HLA-B*2704 clearly demonstrate the effects ofpolymorphisms in the heavy chain on the movements of non-anchoring side chainswithin the peptide and solvent molecules. This view of the dynamics of the solventmolecules in the C-terminal binding region of the molecule demonstrates how thesolvent “bed” may aid closely related MHC molecules to bind the same peptide. In