Ion-Channels: Goals for Function-Oriented Synthesis

Abstract

Ion channels provide a conductance pathway for the passive transport of ions across membranes. These functional molecules perform key tasks in biological systems such as neuronal signaling, muscular control, and sensing. Recently, function-oriented synthesis researchers began to focus on ion channels with the goal of modifying the function of existing ion channels (ion selectivity, gating) or creating new channels with novel functions. Both approaches, ion channel engineering and de novo design, have involved synthetic chemists, biochemists, structural biologists, and neurochemists. Researchers characterize the function of ion channels by measuring their conductance in samples of biological membranes (patch clamp) or artificial membranes (planar lipid bilayers). At the single molecule level, these measurements require special attention to the purity of the sample, a challenge that synthetic chemists should be aware of. Ideally, researchers study the function of channels while also acquiring structural data (X-ray, NMR) to understand and predict how synthetic modifications alter channel function. Long-term oriented researchers would like to apply synthetic ion channels to single molecule sensing and to implantat these synthetic systems in living organisms as tools or for the treatment of channelopathies. In this Account, we discuss our own work on synthetic ion channels and explain the shift of our research focus from a de novo design of oligo-THFs and oligo-THF-amino acids to ion channel engineering. We introduce details about two biological lead structures for ion channel engineering: the gramicidin β(6,3) helix as an example of a channel with a narrow ion conductance pathway and the outer membrane porins (OmpF, OmpG) with their open β-barrel structure. The increase and the reversal of ion selectivity of these systems and the hydrophobic match/mismatch of the channel with the phospholipid bilayer are of particular interest. For engineering ion channels, we need to supplement the single-point attachment of a synthetic modulator with the synthesis of a more challenging two-point attachment. The successful function-oriented synthesis of ion channels will require interdisciplinary efforts that include new electrophysiology techniques, efficient synthesis (peptide/protein/organic), and good structural analysis.

Mechanism of OmpG pH-Dependent Gating from Loop Ensemble and Single Channel Studies

“…As OmpG possesses a unique monomeric structure, it has become attractive as a nanopore sensor compared to other classic trimeric porins OmpF and OmpC. 14,18–20 Our recent works have demonstrated the use of OmpG gating behavior for highly specific protein homologue sensing. 19,21,22 Thus, understanding of OmpG gating may also guide the design of OmpG-based nanopore sensors for new applications.…”

Aminobenzoic acid incorporated octapeptides for cation transport

“…[1][2][3] The limitations associated with the stability and characterization of large proteins, inspires researchers to develop oligopeptides capable of ion-selective membrane transport. [4][5][6] Non-toxic low molecular weight peptidic ion transporters are potentially useful for pharmaceutical applications as well as attractive model systems for gaining mechanistic insights into membrane transport through larger proteins. A variety of the small oligopeptide ion transporters are derived from cyclic peptides comprising alternating D-and L-amino acids.…”

Realizing Synchronous Energy Harvesting and Ion Separation with Graphene Oxide Membranes

“…In biological systems, ion-selectivity can be achieved by the delicate interactions between ions and amino acids123456. Specifically, proteins primarily utilize two types of interactions to recognize different ions: the coordination between transition metal cations and oxygen-containing functional groups78910, and the non-covalent cation-π interactions between main group cations and aromatic side chains11121314.…”