computer modeling in molecular biology.pdf

3 Molecular Dynamics Simulations of Peptides 513.3.5 Melanin Concentrating Hormone (MCH)MCH is a neuropeptide produced in the hypothalamus. In teleosts it concentratesmelanin within the pigment cells of the skin [26], hence causing the fish skin to appearpaler, but it is not a simple antagonist of melanin stimulating hormone (MSH).It also induces melanosome dispersion within tetrapod melanophores [27]. MCHalso acts as a potent pituitary hormone, inhibiting the release of ACTH in mammals[28], and stimulating growth hormone release in rats [29]. Although it has beenshown to be present in man its function in man is, as of yet, unknown. MCH is anoligopeptide of 17 residues with the sequence:Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-ValA disulphide bridge between Cys' and Cys14 forms an intramolecular ring of 10residues.From an arbitrary starting conformation, built using molecular graphics such thatthe Cys-Cys disulphide could be made, we generated a total of 150 picoseconds ofmolecular dynamics trajectories on MCH and the 2 fragments, the cyclic MCH5-14ring and the linear MCH,-,, fragment [30, 311. The next stage of the moleculardesign procedure is to determine the local minima being passed through. This is doneby taking the instantaneous coordinates every picosecond and minimising each ofthese structures. One of the major features of these conformations is an internalcross-ring hydrogen bond from the Tyr" side chain hydroxyl to the backbone carbony1of Cys' which may, to a certain extent, be responsible for the rigidity of thering. In all the conformations we generated we found that the largest conformationalchanges occured in the GlyE-Argg region. Some regions of the peptide were seen tobe constrained in the simulations. One such area was the section Val" to Cys14,around the Pro'3 residue. A sample minimised conformation of cyclic MCH,-,,showing the cross-ring hydrogen bond is given in Figure 3-3.Thus, from the molecular dynamics we have been able to identify conformationallyconstrained features and regions of conformational flexibility of MCH,which may have bearing on the conformation required for activity. It should benoted these studies have been carried out as part of experimental programs, whichis important for many biological systems as modelling with limited information mustalways be checked against experimental data and structural hypotheses tested by synthesis(see [30-321 for full details).At this stage of the investigation, we cannot determine which of the conformationsmay be the binding or active conformations. Additional information, from aknown antagonist or additional agonists or inactive compounds, is needed before wecan make a more specific prediction of the active conformation.