(739i) Mechanisms of Synthetic Chloride Ion Transporters in Lipid Bilayer Membranes

Natural lipid bilayer membranes are impermeable to many biologically relevant molecules and atomic species. Special transmembrane protein complexes embedded in lipid bilayers facilitate the transport of physiologically necessary molecules across the barrier. For this reason, when diffusion rates and concentration gradients across a cell membrane must be precisely regulated, protein complexes are often involved. Intracellular concentration of ions are commonly regulated by these complexes. Chloride channels comprise a superfamily of protein complexes specific for the chloride ion gated by one of four main mechanisms — membrane potential, Ca⁺² ion gradient, ligand, or pH. Dysfunction in these channels is responsible for several serious human pathologies including cystic fibrosis. SCMTR’s (Synthetic Chloride ion Membrane TRansporters) are a class of designer molecules that mimic the function of natural chloride channels, exhibiting voltage gated transport of chloride ions across artificial lipid membranes. Previously, the mechanisms by which these synthetic transporters operated were poorly understood. New molecular dynamics simulations of SCMTR’s in lipid membranes of pure DOPC and 50/50 mixtures of DOPC/DOPE have uncovered the mechanisms of channel formation and voltage gating. A recently developed method, known as computational electrophysiology, allows for the simulation of ion flux under a constant ion concentration gradient and thus a constant voltage. Simulated channel current and ion flux compare well to experimentally observed values. Animations of molecular dynamics simulations provide a better qualitative mechanistic understanding of channel formation and ion permeation and gating processes.