computer modeling in molecular biology.pdf

~443.3.1D. J. Osnuthorpe and I? K. C. PaulPharmaceutical Applications ofConformational Studies of PeptidesA very common problem in the pharmaceutical industry is how to determine the conformationalrequirements for activity in systems where the structure of the receptoris not known. Much time and effort has been devoted to this problem. Here we concentrateon the application of molecular dynamics to this problem and look at thespecific example of peptide hormones, systems which are very difficult to handlewith standard methods because of the highly flexible nature of peptides. Two examplesof peptide hormones that we have studied will bring out the techniques andthe information one can get from such studies.Molecular dynamics was first used in this way to study the hormone vasopressin[MI. These procedures were developed based on the idea that conformationalrecognition is the basis of receptor-ligand interactions. Initially the receptorrecognises a “binding” conformation, which the ligand must be able to adopt tobind to the receptor. The receptor may recognise this conformation by looking forthe correct positioning of certain functional groups, the binding groups. This meansthat the ligand has to be able to adopt a certain conformation, one which has thefunctional groups positioned correctly. Following binding, the response is generatedby either a conformational change occurring in the ligand-receptor complex (whichinvolves the ligand) or the correct positioning of certain functional groups (the activegroups). Thus, agonists are capable of undergoing this conformational change orthey have the active functional groups, whereas antagonists do not.Therefore, if we find the accessible conformations of a peptide hormone andthose of an antagonist, and then perform a structural cross comparison of these twosets of structures, conformations that both the peptide and antagonist adopt areputative binding conformations whereas conformations that agonists adopt but antagonistsdo not are putative conformations necessary for activity. We have usedmolecular dynamics simulations to access the conformational space of a molecule,and use the resulting minimised conformations to give us pointers to the molecule’sfunction. In this case we are simply using the properties of molecular dynamics tosearch conformational space in an energetically directed manner. This is not a“simulation” of the molecular properties of the system, but a means to determinewhich conformations the trajectory has passed through. Hence we can use hightemperatures and we do not have to worry about equilibration, indeed it is better touse the non-equilibrated parts of the trajectory. We use two major methods of tracingaccessed conformations. The first one is to follow the conformational transitionsin the molecule by plotting backbone torsional angles like a, and t,u of key or “interesting”residues and minimising from that point in the trajectory. The secondmethod is to periodically minimise conformations accessed during the simulation atsay every 5.0 or 1 picosecond and cluster them into families depending on rms devia-