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desalination and membranes refereed paper AQUAPORINS – USEFUL LEADS TO LOW ENERGY DESALINATION MEMBRANES? B Bolto, M Hoang, T Tran Abstract The 2003 Nobel Prize in Chemistry was awarded to Agre and MacKinnon, who contributed to the fundamental chemical knowledge on how cells function. They discovered a system of molecular reticulation in cell membranes: channels, gates and valves all of which are needed for cells to function. It is an excellent model for designing the ultimate in practical low energy, high flux desalination membranes that transport water, but not salt. Introduction Water crosses cell membranes by two routes: diffusion through a liquid bilayer, or diffusion through water channels called aquaporins. Progress in understanding the structure and function of aquaporins has been rapid, with the topic being the subject of detailed reviews (Agre et al., 2002; Beitz, 2009). Aquaporins transport solute-free water across cell membranes via exclusive water channels that are not permeable to ions or other small molecules. More than ten different mammalian aquaporins have been identified to date (Nobel Foundation, 2003). They are composed of proteins of molecular weight ~28,000 Da, are very widely distributed and have different important specific functions. Aquaporin-1 from human red blood cells was the first to be discovered and is the most studied; it exists in the kidney, eye, brain and lung. Each pore facilitates water transport through the cell membrane at the rate of three billion water molecules per second, in a movement that appears to be bidirectional depending on the osmotic gradient. Based on hydrophobicity and plots of the amino acid sequences of the proteins, aquaporin units are predicted to have six membrane-spanning segments, as shown in Figure 1 for aquaporin-1, which is known as AQP1. This aquaporin appears to exist as a tetramer or four such units, with each aquaporin monomer containing two hemi-pores which fold onto each other in a unique 80 AUGUST 2010 water Figure 1. Postulated structure of aquaporin-1 (adapted from King and Agre, 1998). way to form the water channel. There are thus four channels per structure. To maintain an even pressure in the cells it is important that water can pass through the cell wall, as has been known for a long time. The appearance and function of these pores remained one of the classical unsolved problems of biochemistry. It was not until around 1990 that the first water channel was discovered. Like so much else in the living cell, a protein was the dominant factor. Water molecules are not the only entities that pass into and out of the cell. For billions of cells to be able to function collaboratively, coordination is required, so communication between the cells is necessary. The signals sent in and between cells involve ions or small molecules. These start cascades of chemical reactions that control all our bodily functions. The signals in the brain also involve such chemical reactions. As early as the middle of the nineteenth century it was understood that there must be openings in the cell membrane to permit a flow of water and salts. In the middle of the 1950s it was discovered that water can be rapidly transported into and out of cells through pores that admit water molecules only. During the next 30 years this was studied in detail and the conclusion was that there must be some type of selective filter that prevents ions from passing through the membrane, while uncharged water molecules flow freely. Although this was known, it was not until 1992 Can man emulate nature? that the molecular machinery was identified as to which protein or proteins formed the actual channel. In the mid1980s Agre studied various membrane proteins from red blood cells and cells in the kidney (Nobel Foundation, 2003). The hypothesis was tested in a simple experiment where cells that contained the protein in question were compared with cells that did not have it. When the cells were placed in a water solution, membranes containing the protein absorbed water by osmosis and became swollen, while those that lacked the protein were not affected. Trials were also run with artificial cells, or liposomes, which are really surfactant bubbles surrounded on the outside and inside by water. It was found that the liposomes became permeable to water if the protein was planted within their membranes. In 2000, together with other research teams, Agre reported the first highresolution images of the threedimensional structure of the aquaporin. With these data it was possible to map in detail how a specific water channel functions which admits water molecules but not other molecules or ions. Selectivity is a central property of the channel. Water molecules worm their way through the narrow channel of the hour glass structure by orienting themselves in the local electrical field formed by the charged functional groups in the channel wall. Cations are stopped on the way because of the positive charge at the centre of the channel (Figure 2), which rejects like-charged species such as hydrated protons which would otherwise cause a pH change. technical features desalination and membranes Studies of the water channel aquaporin-Z from E. coli have shown that it transports less than one ion per 109 water molecules (Pohl et al., 2001). Structural Details of Water Channels Hundreds of proteins have been identified in water channels from all forms of life (Fujiyoshi et al., 2002). The strict selectivity for water raised many questions about the structural basis Figure 2. Passage of water molecules through an aquaporin responsible for these from Nobel Foundation, 2003). remarkable properties. The structure is based on a motif centre of the pore, thus inhibiting the or sequence of three specific amino permeation of cations (Law and Sansom, acids (asparaginine, proline and alanine, 2002). abbreviated as NPA) and the unique During the past ten years, water aquaporin fold. channels have developed into a highly The three amino acids are of different topical research field. The aquaporins types: the first is hydrophilic and polar, have proved to be a large protein family. and the other two are hydrophobic. They exist in bacteria, plants and Mutation of residues around the NPA animals. In the human body alone at least motif reduces water permeability, eleven different variants have been suggesting that these regions contribute found. The function of these proteins has to formation of the aqueous pore (Jung et now been mapped in bacteria and in al., 1994). Also relevant among many plants and animals, with a focus on their others are seven further amino acids physiological role. In humans, the water (valine, isoleucine, leucine, phenylalanine, channels play an important role in, cysteine, arginine and histidine). among other organs, the kidneys. The Molecular dynamic simulations of water kidney is an ingenious apparatus for permeation through AQP1 show that disposing of substances the body wishes water molecules are strongly oriented in to remove. In its windings or glomeruli, the channel interior, with their dipoles which function as sieves, water, ions and rotating about 180° during flow through other small molecules leave the blood as the channel (Murata et al., 2000). There is primary urine. Over 24 h, about 170 L of a large tilt of about 30° of the α-helices primary urine is produced. Most of this is that embrace the central pore region, re-absorbed by a series of mechanisms where the NPA motifs contact each other so that finally about 1 L of urine a day (Fujiyoshi et al., 2002). The right-handed leaves the body. From the glomeruli, arrangement of the α-helices was initially primary urine is passed on through a controversial, but other examples of winding tube where about 70% of the strongly tilted ones have since emerged. water is re-absorbed into the blood via Many helix-helix interactions stabilise the aquaporin AQP1. At the end of the tube, system. Water-water hydrogen bonds are another 10% of water is re-absorbed with weakened at the narrowest part of the a similar aquaporin, AQP2. pore, 0.2 nm across. This suggests that the NPA region is a major selectivity filter. The midpoint of the rotation of the water molecules is located in this NPA region. About half of the channel wall along the selectivity filter can be considered hydrophobic and the other half hydrophilic (Sui et al., 2001). The hydrophilic face provides the sites that are essential for displacing certain waters of hydration, thereby establishing a pathway for coordinating water transport. The terminal amino groups of the NPA loop might be expected to form a region of positive electrostatic potential in the 82 AUGUST 2010 water Channels exist that can admit and transport ions. There is a well-developed knowledge of the central functions of ion channels, which are able to admit one ion type selectively, but not others. Cells must also control the opening and closing of the ion channels. This is achieved by a gate at the bottom of the channel which is opened and closed by a molecular sensor, situated near the gate. Certain sensors react to certain signals, such as the binding of a signal molecule of some kind, an increase in the concentration of calcium ions, or an refereed paper electrical potential over the cell membrane. For example, L-glutamate is the major neurotransmitter in the mammalian central nervous system, acting in one way through ligand-gated ion channels, or ionotropic receptors (Bristol University, 2003). Implications for Water Treatment There is undoubtedly much to learn yet about aquaporins at a basic mechanistic level. (adapted Nevertheless, work is proceeding on ways of incorporating aquaporins into membranes that are aimed at improving permeability, which for an aquaporin saturated lipid membrane is claimed to be more than 100-fold that of normal water treatment membranes (Jensen et al., 2006, using data of Pohl et al., 2001), obtained with aquaporin membranes of 150 μm diameter. Patents have been filed on water filtration and desalination applications (Jensen et al., 2006; Kumar et al., 2009), and one firm is aiming to release its membrane to the market place in 2011 (Anon., 2010). The intricacies of biological membranes mean that manmade versions of them for desalination purposes are some way off, especially as they will have to avoid the hydrolytic instability of proteins under acid or alkaline conditions. Adequate physical integrity is another hurdle. There is a considerable challenge overall. The open path channel through the species offers a fast flow that is not necessarily impeded by the central constriction in the hour glass pores, as it is of very short depth. Polyimide membranes that have been thermally rearranged have an hour glass configuration (Park et al., 2010). They are useful for gas separations such as CO2 removal from mixtures with methane, where transport of the larger molecule is facilitated, as it has a long thin shape versus the larger roughly shaped spheres for the smaller species. The nearest unfunctionalised analogues so far are carbon nanotube structures that can provide a continuous channel capable of rapid flows. An example of the rapid flow possible, which has been described as slip or frictionless flow, is that achieved with nanotubes with a pore size of 2 nm, which have water permeabilities several orders of magnitude greater than commercial technical features refereed paper desalination and membranes polycarbonate membranes, despite having pore sizes an order of magnitude smaller (Holt et al., 2006). Their usefulness in desalination has been discussed (Corry, 2008). However, constructing membranes from the nanotubes is not a trivial problem. Binding them in a matrix, but ensuring that there is no leakage between it and the fibre, is a major challenge. There is some progress: because of their very high adsorption capacity for salt, oxidised carbon nanotube sheets have been proposed for sea water desalination (Togfighy and Mohammadi, 2010). Fujiyoshi, Y., Mitsuoka, K., de Groot, B., Philippsen, A., Grubmüller, H., Agre, P. and Engel, A. (2002). Structure and function of water channels. Current Opinion in Structural Biol. 12, 509-515. References King, L. S. and Agre, P. (1998). Pathophysiology of the aquaporin water channels. Ann. Rev. Physiol. 58, 619-648. Agre, P., Borgnia, M. J., Yasui, M., Neely, J. D., Carbrey, J., Kozono, D., Beitz, E., Hoffert, J., Leitch, V. and King, L. S. (2002). Discovery of the aquaporins and their impact on basic and clinical physiology. Current Topics in Membranes 51, 1-36. Anon. (2010). Aquaporin receives award for its biomimetic membrane. Membrane Technol., No. 4, 4. Beitz, E. and Agre, P. (2009). Aquaporins, Springer, Berlin. Bristol University (2003). Glutamate receptors – structure and functions. http://www.bris.ac.uk/ Depts/Synaptic/info/glutamate.html Corry, B. (2008). Designing carbon nanotube membranes for efficient water desalination. J. Phys. Chem. 112, 1427-1434. Holt, J. K., Park, H. G., Wang, Y., Stadermann, M., Artyukhin, A. B., Grigoropoulos, C. P., Noy, A. and Bakajin, O. (2006). Fast mass transport throughsub-2-nanometer carbon nanotubes. Science 312, 1034-1037. Jensen, P. H., Keller, D. and Nielsen, C. H. (2006). Membrane for filtering of water. International Patent Application WO 2006 122566. Jung, J. S., Preston, G. M., Smith, B. L., Guggino, W. B. and Agre, P. (1994). Molecular structure of the water channel through aquaporin CHIP: the hourglass model. J. Biol. Chem. 269, 14648-14654. Kumar, M., Clark, M. M., Zilles, J., Brzelakowski, M. Nehring, R. and Meier, W. (2009). Highly permeable polymer membranes. International Patent Application WO 2006 076174. Law, R. J. and Sansom, M. S. P. (2002). Water transporters: How so fast yet so selective? Current Biol. 12, R250-R252. Mishina, M., Sakimura, K., Mori, H., Kushiya, E., Harabayashi, M., Uchino, S. and Nagahari, K. (1991). A single amino acid residue determines the Ca2+ permeability of AMPA-selective glutamate receptor channels. Biochem. & Biophysical Research Communications 180, 813-821. Murata, K., Mitsuoaka, K., Hirai, T., Walz, T., Agre, P., Heymann, J. B. and Engel, A. (2000). Structural determinants of water permeation through aquaporin-1. Nature 407, 599-605. Nobel Foundation. (2003). The Nobel Prize in Chemistry 2003. http://nobelprize.org/ chemistry/laureates/2003/public.html Park, H. B., Han, S. H., Jung, C. H., Lee, Y. M., and Hill, A. J. (2010). Thermally rearranged (TR) polymer membranes for CO2 separation. J. Membrane Sci. in the press; available on line at doi:10.1018/j.memsci.2009.09.037 Pohl, P., Saparov, S., Borgnia, M. J. and Agre, P. (2001). Highly selective water channel activity measured by voltage clamp: Analysis of planar lipid bilayers reconstituted with purified AqpZ. Proc. National Acad. Sci. 98, 9624-9629. Sui, H., Han, B.-G., Lee, J. K., Wallan, P. and Jap, B. K. (2001). Structural basis of water-specific transport through the AQP1 water channel. Nature 414, 872-878. Togfighy, M. A. and Mohammadi, T. (2010). Salty water desalination using carbon nanotube sheets. Desalination 258, 182-186. The Authors Dr Brian Bolto, Dr Thuy Tran and Dr Manh Hoang (email: [email protected]; [email protected]; [email protected]) work for CSIRO Materials Science and Engineering, Clayton, Victoria.