computer modeling in molecular biology.pdf

38 D. J Osmthorue and I? K. C Paul3.1 IntroductionConformational studies of peptides have a long history, with some of the first calculationsof biological molecules being studies of dipeptides. The first major understandingin the field of peptide and protein conformation came with the finding thatnearest neighbour interactions have an important part to play in shaping protein conformation[l-31. Today with hundreds of protein crystal structures solved it is stillfound that most of the residues fall within the allowed (q, I,U) region of theRamachandran map. The use of energy parameters [2-51 and minimisation techniques[6-81 to search for global minimum energy conformations and the subsequentapplication of molecular dynamics techniques [9] to study conformational transitionsand pathways was the next stage in the understanding of peptide and proteinconformation. Currently, with the advent of more and more sophisticated forcefieldsand integrating algorithms coupled with extremely good graphics visualisation programs,molecular modelling using dynamics simulations is becoming a routine toolin the study of peptides and proteins. The number of molecular dynamics studieson peptides has burgeoned in the last few years. Table 3-1 gives a list (by no meanscomplete) of recent peptide modelling studies. As is evident, the combined use ofNMR data with molecular dynamics simulations is on the increase, and representsa pofverful method to obtain structural pointers in explaining bio-activity.Peptide hormones are currently of great interest as they control many of thehomeostatic mechanisms of animals and humans. By modulating the behaviour ofpeptide hormones with agonists or antagonists, it is possible to control many medicalconditions. There is currently much interest in the pharmaceutical industry in designingdrugs by mimicking the peptide controlling the faulty or diseased biologicalmechanism. We know that hormones bind to a receptor, which is generally a protein,by non-bonding interactions. The receptor is only capable of binding molecules ifthey can adopt a specific conformation, the active conformation. However, the structureof most receptors is generally not known. This is partly because there are onlya small number of receptor molecules per cell, which makes it difficult to get enoughmaterial for structural studies, and partly because many receptors are membraneboundproteins, whose structures are difficult to determine. Our only way out of thissituation, if no receptor structure is likely to be available, is to attempt to “guess”the structure of the active conformation by looking at ligands which are known tobind to the receptor. Since peptide hormones are highly flexible, a major part ofdesigning the drug is to find out what is the “active conformation” of the hormone,by investigating the energetically accessible conformations of the hormone and itsanalogues.