1.D.101. The Ligand-gated Pi-stacked Synthetic Ion Channel (LPSIC) Family
Supramolecular pi-stack architecture is fundamental in DNA chemistry but absent in biological and synthetic ion channels and pores. Talukdar et al. 2005 characterized a novel rigid-rod pi-stack architecture, introduced to create synthetic ion channels with characteristics that are at the forefront of rational design, that is, ligand gating by a conformational change of the functional supramolecule. The intercalation of electron-rich aromatics is designed to untwist inactive electron-poor helical pi-stacks without internal space into open barrel-stave ion channels. Conductance experiments in planar lipid bilayers corroborate results from spherical bilayers and molecular modeling. Highly cooperative and highly selective ligand gating produces small, long-lived, weakly anion selective, ohmic ion channels. Structural studies conducted under conditions relevant to function provided experimental support for a helix-barrel transition as the origin of ligand gating. Control experiments demonstrated that minor structural changes leading to internal decrowding suffice to cleanly annihilate chiral self-organization and function.
Sakai et al. 2006 pointed out the central role of the exciton chirality method to gain insights into the structural basis of the ligand gating of synthetic ion channels. Ligand gating was achieved with an equally unprecedented transmembrane rigid-rod pi-stack architecture that is designed to adopt a closed conformation with helically stacked naphthalenediimide (NDI) acceptors. The intercalation of the complementary electron-rich dialkoxynaphthalene ligands then stimulated the untwisting of the closed pi-helices into hollow barrel-stave supramolecules. During this helix-barrel transition, the angle between the transition moments of the exciton-coupled NDI chromophores decreases toward zero. The corresponding disappearance of the split CD provides, according to the exciton chirality method, the otherwise elusive experimental support that ligand-gated ion channel formation really occurs by this rationally designed helix-barrel transition.