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IISER Pune scientists design first synthetic ion channel that allows hopping of anions   Sep 16, 2015

Ions are used in various biological processes to relay messages from one cell or tissue to another. For this they need to move across the cell membrane. This transport is facilitated by certain complex proteins that form channels across the lipid bilayer, through which the ions can pass. Some channel proteins have multiple recognition-and-binding sites spread over their length. Ions ‘hop’ from one such binding site to the next in single-file, gradually permeating into the cell. For ion channels to be biologically useful, ‘selectivity’ is paramount. That is, a channel must show a higher preference for the passage of a specific type of ion. This selectivity depends on strength of the ion-binding interactions at recognition sites of the channel.

Dr Pinaki Talukdar’s lab at IISER Pune is involved in synthesis and self-assembly of organic molecules in the lipid membrane to form artificial ion channels. According to him, "Such artificial channels with specific selectivity can have potential applications in areas like medicinal chemistry and drug discovery." The present goal of his lab is to design synthetic molecules which preferentially transport chloride (Cl-), the most abundant and essential anion (negatively charged ion) in living systems.

Numerous synthetic channels with multiple recognition-and-binding sites for cations (positively charged ions) have been previously designed. However, artificial ion channels selective for anions are rare. Dr Talukdar, in collaboration with three other scientists, decided to address this lacuna. Working at three different research organizations in the country, each of these four principal investigators brought his own expertise to the table. Their collective effort has resulted in development of the first artificial, small organic molecule-based, anion selective channel with multiple recognition-and-binding sites.

Dr Talukdar and his colleagues analysed several motifs and envisaged that hydroxyl (–OH) groups might be involved in recognition of anions. They focussed on a derivative of D-mannitol (an alcohol of D-mannose sugar) that contains two free hydroxyl groups and can self-assemble to form long fibrils of repeating units connected to each other like a chain.

Dr Talukdar’s experiments show that in a lipid bilayer membrane, aggregates are formed of three such fibrils assembled face-to-face in a nanotubular structure resembling a channel. Since it is made up of three chains of molecules, the aggregated structure can be viewed as multiple layers of ‘rosettes’, each formed by three units of the mannitol derivative. A chain of approximately seven layers of rosettes spans the lipid membrane. Each rosette provides hydroxyl groups which an anion can recognize and bind via hydrogen bonds. The anions can thus move across the lipid membrane, by ‘hopping’ from one rosette to the next in single file. Dr Talukdar has hypothesized that in addition to anion binding, the –OH group also has another function. “We believe that the hydroxyl groups play an important role in structurally stabilising the backbone of the nanotube through a network of hydrogen bonding interactions”, he states.

Using a pH-sensitive fluorescent dye, Dr Talukdar and colleagues demonstrated that these nanotubes can transport ions across a lipid bilayer in a concentration-dependant manner. They showed that their channel specifically allows only anions to go through. Significantly, the channel shows highest selectivity for the chloride ion. When Cl- moves through the channel, loss in enthalpy (heat content) is small as the ion remains partially hydrated within the nanotube. At the same time, there is a large enthalpy gain through strong hydrogen bonding interactions with each rosette. “This rationalizes the selectivity of our channel for chloride ion”, explains Dr Talukdar.

Model of three rosettes with a Cl- ion

Anion selectivity of the channel

Computer-based modelling studies carried out by Dr Arnab Mukherjee (Assistant Professor, IISER Pune) confirm these observations. Using simulations, the scientists have worked out the molecular mechanism and speed of anion transport through the channels. Their study reveals that ‘hopping’ of the Cl- ion from one rosette to the next occurs through an intermediate bridged state in which the ion is bound to rosettes on both sides. “We call this the ‘relay mechanism’ during hopping”, says Dr Talukdar.

Potential applications of this new molecule include therapeutic replacement of defective Cl- channels in certain diseases and development of anti-cancer and antibacterial agents. Dr Talukdar plans to improve the activity of such channels by designing new mannitol-derived molecules. Along with his collaborators, he also plans to research how hydroxyl groups can be used to enhance the stability of such artificial ion channels.

Model of the channel with a chloride ion in DPPC/water

This work has been published in Journal of the American Chemical Society as a research paper titled “Hopping-Mediated Anion Transport through a Mannitol-Based Rosette Ion Channel” (J. Am. Chem. Soc.2014136:14128-14135). It has been authored by Pinaki Talukdar along with Tanmoy Saha, Sathish Dasari, Arnab Mukherjee (IISER Pune, India); Annamalai Prathap, Kana M. Sureshan (IISER Thiruvananthapuram, India); and Debanjan Tewari, Amal K. Bera (IIT Madras, Chennai, India).

You can learn more about Dr Pinaki Talukdar’s research here.

Image Credits: Dr. Pinaki Talukdar