Aquaporins are water channel proteins; they are located in the otherwise waterimpermeable cell membrane of many plants and animals. There they prevent bursting of the cells, e.g., due to changes of the exterior salt concentration (osmotic regulation). In humans, aquaporins regulate the water flux in the kidney, red blood cells, the eye lens, and the brain, to name just a few. Accordingly, defects in these proteins are known to be involved in a number of diseases, e.g. diabetes insipidus, congenital cateract, and impaired hearing.
In all cases, a highly efficient, yet selective water transport, that excludes permeation of other molecules, is of central importance. As filters of the cell, aquaporins prevent the loss of e.g. sugar molecules or ions. Despite this high degree of selectivity, aquaporins reach a remarkable efficiency of up to three billion water molecules per second and channel. A membrane patch of 10x10 cm2 with embedded aquaporins could filter 1 liter of water in about 7 seconds.
How are these conflicting requirements realized? First hints came from an atomic model of the structure of an aquaporin (AQP1) that was recently solved by electron microscopic techniques in a collaboration between the Japanese group of Yoshinori Fujiyoshi, the Basel group of Andreas Engel and the Göttingen Max Planck group for Theoretical Molecular Biophysics. The structure showed that the protein forms a channel in the membrane that is 2 nanometers (billionth meter) long and 0.3 nanometers wide, just large enough for water molecules to fit through, such that permeation of larger molecules is prevented.
The main problem, that apparently has been solved by evolution, is: How can also the permeation of smaller ions be blocked? In particular, prevention of proton (hydrogen ion) permeation is of crucial importance since a difference in proton concentration (pH) between the cell interior and exterior is an important short-time energy storage ¾ like an electrical battery ¾ which would otherwise be short-circuited. Water itself is known to conduct protons well; protons can hop via so-called hydrogen bonds from one water molecule to the next. So, how does aquaporin prevent proton hopping through the channel?
The static structure of the channel only allowed to speculate about this question. In particular, it did not allow the observation of the movements of water molecules through the channel. It also leaves the issue of the extraordinarily large water permeability unresolved.
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Scientists from the Theoretical Molecular Biophysics Group at the Max Planck Institute for Biophysical Chemistry now succeeded to trace, in 'real-time', individual water molecules on their way through an aquaporin channel by using atomic resolution computer simulations. For these simulations, the atomic structure of the protein was embedded within a virtual bilayer membrane and surrounded by a large number of water molecules (Fig. 1), the protein's natural environment.
The so-obtained computer-model contained approx. 100.000 atoms, of which the movements were accurately calculated by means of so-called molecular dynamics simulations. Several months of calculations on an 80 processor parallel computer were required for the simulation. A 'movie' was obtained in this way that allowed the observation and analysis of the permeation of individual water molecules through the channel at any desired resolution (Fig. 2). The water permeation rate observed in the simulation was found to correspond well to experimental values, an important test for the accuracy of the simulation.
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The simulations revealed a fascinating, delicately choreographed 'dance' of the water molecules, directed by carefully positioned protein parts (amino acids) at the channel interior. This precise control of the movements of water molecules was found to have a twofold function. First, water molecules are 'passed on' in an ordered way on their way through the channel, which drastically increases the water permeation rate. Second, the permeation of protons is blocked by breakage of hydrogen bonds between passing water molecules. Such breakage would usually be energetically unfavorable (this effect makes that water boils at a temperature of 100oC, whereas carbon dioxide boils already at -78 oC). Aquaporin compensates for this energetic cost by a highly ordered formation of transient hydrogen bonds with passing water molecules. The permeation of water molecules therefore is a spectacular example of biological molecular nano-engineering.
In a follow-up project, the Göttingen group is involved in an international collaboration, sponsored by the European Union, to try, find and test molecules in simulations that could regulate or block aquaporins. Such molecules would be an important advancement in the development of new drugs.
Computer simulations of proteins at the atomic level are currently being applied with increasing success, facilitated also due to rapidly increasing computer power. Going beyond traditional bioinformatics, such simulations promise a thorough physical and chemical understanding of the underlying biological functional processes.
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