computer modeling in molecular biology.pdf

3 Molecular Dynamics Simulations of Pevtides 53interaction with the environment and have done this very successfully. Using natureas a model, we can look for analogues of the systems we would like to develop asmolecular devices. One important function required is a switch which acts on someinformation flow. An important switch in nature is the ligand gated ion-channel,which is found in many organs but in particular is an important component of braincells. A switchable ion channel could form the basis of molecular electronics componentsbased on ion gating, rather than electron gating.Switchable transmembrane ion channels are used in nature to control ion concentrationson either side of a membrane. One of the best-studied ion channel familiesare the ligand-gated ion channels [33] of the which the most studied member is thenicotinic acetylcholine receptor. From experimental studies of this channel, the ionchannel is believed to involve four a-helices which pack together in a helix-bundletype arrangement to form a central channel. From amino-acid sequence informationof the ion channel, model a-helices have been created which suggest that the polaramino-acids of these helices aggregate on one face and the apolar amino-acids onthe opposite face. Synthetic peptide ion channel models based on these native sequencesalso have a similar positioning of polar and apolar amino-acids. Such peptideshave been shown to act as short life-time channels in synthetic lipid bilayersP41.Hence, we wished to design novel peptides which would form stable a-helices inmembranes and would aggregate to form a helix-bundle which would allow ions topass through a central channel. Our primary design suggestion was to add hydrophilicpolyethoxy spacers to link the hydrophilic residues (Ser) of the synthetic sequencebased on the natural ion channel which showed channel activity. A numberof question were raised by this suggestion for which we used molecular dynamicssimulations to find answers. Two main questions were: What length of spacer wouldstabilise the helix with the least perturbation of the helix structure? and How manyof these helices would form the bundle best able to transport ions?3.3.7 Molecular Dynamics Calculationson Synthetic Ion ChannelsSimulations were performed on synthetic ion channels having 4, 5 and 6 helicalbundles of (LSSLLSL)*3 peptide with and without bridging spacers between theSer-2 and Serd of each LSSLLSL fragment. All the helices were aligned parallel toeach other in the starting conformations. The initial conformation for the residueswas set to a (p, ty) of (- 57, - 47). In addition, in the case of the four helix bundlean anti-parallel arrangement was tried. Also a simulation of the four helix bundlewithout spacers but including three Na ions within the channel was attempted. Thus