computer modeling in molecular biology.pdf

3 Molecular Dynamics Simulations of Peptides 49tive, however, the methylated analogue showed considerable activity [25]. Thus thedesign of an analogue based on the molecular dynamics calculations confirms ourstructural predictions regarding the location of the 0-turn and its overall influencein the structure.3.3.4 LHRH AgonistsThis leads to the following question. Is the conformation of LHRH proposed earlierfrom energy calculations [19, 201, i. e. the one with a 5-8 p-turn a truly low energyconformation? Constrained molecular dynamics on LHRH was performed startingwith conformations forced to adopt /?-turns between residues 2-5, 3-6, 4-7 and 5-8.All possible types of p-turns, appropriate to the sequence of the middle residues weretried in the calculations. Thus the starting conformations consisted of(a) a type I His2-Trp3 p-turn(b) a type I Trp3-Ser4 p-turn(c) a type I Ser4-Tyr’ /?-turn(d) a type I Tyr5-Gly6 p-turn(e) a type I1 Tyr5-Gly6 p-turn(f) a type I Gly6-Leu7 p-turn(8) a type 11’ Gly6- Leu7 8-turn(h) an extended conformationThe simulations were performed for 50 ps each, at 600 K, and the conformations accessedsampled at appropriate intervals. The results are shown in Table 3-2. Thelowest energy conformations do indicate some p-turn character between residues 5to 8 though without the associated 4-1 hydrogen bond, vindicating the earliercalculations on LHRH. Conformations with a hydrogen bonded p-turn betweenresidues 3 to 6 (which were found to be low energy conformations in the antagonistseries) are about 10 kcal/mol higher in energy. The calculations were extended to D-and LAla6 substituted LHRH analogues and it was found that a 5-8 type 11’ pturnconformation is indeed the one with the lowest energy conformation. Though boththe analogues can adopt this P-turn the D-Ala analogue is about 6 kcal/mol lowerin energy than the GAla analogue.Why is this apparent predilection of agonists for one type of p-turn and for themost potent antagonists known to date to adopt another type? One possibility is thatthe in the antagonist conformations with the 3 -6 p-turn though the binding is goodthe effector system is not triggered owing to the different sidechains that come tobear on the receptor. Whereas in the agonist with a 5-8 type II’ &urn it is someother residues that interact with the receptor which is responsible for gonadotropinsecretion. In the absence of a structure for the LHRH receptor all this will remainhighly speculative.