Molecular Dynamics Studies of Homo-Oligomeric Ion-Channels

Ion-channels embedded within biological membranes help maintain osmotic equilibrium, facilitate bioenergetics, and provide the means for transmitting environmental signals. For the rational design of new therapeutics, it is imperative to understand ion-channels interactions in the ‘interfacial' region between the aqueous phase and the hydrophobic core of the bilayer. using molecular dynamics simulations of synthetic LS2 and LS3 channels ranging from 1-6 peptides, the structural dynamics of alpha-helices in their membrane environment was characterized. Results show that higher order bundles do not remain in a symmetric packing arrangement but rather form lower order bundles that interact with each other. For example, the LS2 channel is most stable as a tetrameric bundle that is composed of a “dimer of dimers”, while the LS3 channel is most stable as a hexamer comprised of a “dimer of trimers”. In addition, lipid perturbation was found to be strongest for bundles consisting of three or less peptides, where it was found that there is a strong correlation between the tilt angles of the helix/helices of each system with the hydrophobic lipid mismatch and the lipid orientational distribution. These structural results affect the flux of water through the channel, where LS2 was found to have the a maximul flux of water as a tetrameric structural arrangement while water flux through LS3 was maximul as the hexameric arrangement, in agreement with experiment. By understanding the interactions of ion-channels embedded within the membrane, it provides pivotal information in the design of antimicrobial, antiviral, and pharmaceutical agents that target ion-channels.