computer modeling in molecular biology.pdf

48 D. J. Osguthorpe and I? K. C. Paulformational searches and previous studies. A master list of accessible conformationsfor the peptide and its cyclised analogue was compiled. Each of the compounds wastemplate forced onto all conformations, thus investigating the ability of eachanalogue to adopt these conformations. A consistent trend emerged indicating that,for this series of analogues, a p sheet structure with a turn at residues 3-6 is motfavourable. All structures with a 5-8 turn were of higher energies.In the preferred structure that emerged from these simulations the N and C terminalsare in close proximity. This suggested that the next step towards a more activeantagonist might be to join the two ends by an arnide bond. Calculations [25] showedthat the bicyclic analogue maintained the preference for a 3-6 rather than a 5-8 turn.In addition, any other possible patterns of hydrogen bonding consistent with a p-sheet structure were ruled out by using an N-methyl residue at position 10. The stableconformation for this analogue is depicted in Figure 3-2. The two bicyclic analogues,with D-Ala" and with D-MeAla" were synthesised. The first analogue was not ac-Figure 3-2. Proposed bicyclic analogue of LHRH based on the results of molecular dynamicsconformational searching.