computer modeling in molecular biology.pdf

3 Molecular Dynamics Simulations of Peptides 45tions. We have found the former technique useful for constrained systems like cyclicpeptides with the latter being more useful for linear molecules with a lot of conformationalflexibility. Other parameters to use to follow the overall shape of themolecule include end-to-end distance, radius of gyration and moment of inertia.3.3.2 Luteinising Hormone Releasing Hormone (LHRH)LHRH is a decapeptide synthesised in the hypothalamus which on arrival at theanterior pituitary gland, selectively stimulates the release of gonadotropins LuteinisingHormone (LH) and Follicle Stimulating Hormone (FSH). These glycoproteins inturn stimulate the gonadal production of sex steroids and gametogenesis respectively.In 1977 the Nobel prize was awarded to Drs. Schally and Guillemin for the isolationand chemical characterisation of LHRH. The chemical structure elucidation ofLHRH was a major breakthrough in peptide chemistry and LHRH was found to havethe sequence p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. LHRH supposedlyhas a half life of 3 to 6 minutes in the hypothalamic-pituitary blood portal circulationand is degraded by a combination of endopeptidases acting at 5r5-Gly6, enzymesthat hydrolyse p-Glu and enzymes that cleave the carboxyl side of Pro.Not long after the sequence of LHRH was first established and its synthesis successfullyperformed, analogues were made which turned out to be (a) superagonistsor (b) mild antagonists. In the case of agonists the replacement of Gly6 by hydrophobicD-residues had the greatest impact on its activity as did substitutions at theC-terminal end. Most of these analogues turned out to be superagonists. Howeverwhen Gly6 was replaced by L residues there was a considerable drop in activity. Thisled to the implication that, while resistance to enzymatic activity may be responsiblefor the increased potency by substitution of the Gly at the C-terminal end, it is theconformational constraint provided by the D-Ala6 residue while binding to thereceptor that is responsible for the superagonist action. Superagonist analogues arenow commercially available and have a variety of clinical applications.Since the receptor of this hormone is not known, the “active conformation” hasto be deduced from data about the hormone and putative agonists and antagonists.The working hypothesis is that the hormone, its agonists and antagonists all havecommon conformational features which are necessary for binding to the receptor.The hormone and its agonist (but not antagonists) have additional features whichelicit the receptor’s biological response. The possibility of using an LHRH antagonistto control fertility and also treat hormonal disorders had spurred the searchfor a highly potent long acting low toxicity analogue. To this end thousands of antagonistanalogues of LHRH, incorporating various substitutions at different positionsin its sequence have been made and tested. Furthermore, over the years the bindingand activity of the analogues have increased by several orders of magnitude with