Aquaporin water channels: atomic structure molecular dynamics meet clinical medicine.
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ABSTRACT:
SUBMITTER: Kozono D
PROVIDER: S-EPMC151002 | biostudies-literature | 2002 Jun
REPOSITORIES: biostudies-literature
Publications
Aquaporin water channels: atomic structure molecular dynamics meet clinical medicine.
Kozono David D Yasui Masato M King Landon S LS Agre Peter P
The Journal of clinical investigation 20020601 11
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Project description:Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and many functions for AQPs have been reported in health and disease. AQP expression is linked to numerous pathologies including tumor metastasis, fluid dysregulation, and traumatic injury. The targeted modulation of AQPs therefore presents an opportunity to develop novel treatments for diverse conditions. Various techniques such as video microscopy, light scattering and fluorescence quenching have been used to test putative AQP inhibitors in both AQP-expressing mammalian cells and heterologous expression systems. The inherent variability within these methods has caused discrepancy and many molecules that are inhibitory in one experimental system (such as tetraethylammonium, acetazolamide, and anti-epileptic drugs) have no activity in others. Some heavy metal ions (that would not be suitable for therapeutic use) and the compound, TGN-020, have been shown to inhibit some AQPs. Clinical trials for neuromyelitis optica treatments using anti-AQP4 IgG are in progress. However, these antibodies have no effect on water transport. More research to standardize high-throughput assays is required to identify AQP modulators for which there is an urgent and unmet clinical need.
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Project description:Aquaporin-4 (AQP4) is the predominant water channel in the central nervous system, where it has been reported to be involved in many pathophysiological roles including water transport. In this paper, the AQP4 tetramer was modeled from its PDB structure file, embedded in a palmitoyl-oleoyl-phosphatidyl-choline (POPC) lipid bilayer, solvated in water, then minimized and equilibrated by means of molecular dynamics simulations. Analysis of the equilibrated structure showed that the central pore along the fourfold axis of the tetramers is formed with hydrophobic amino acid residues. In particular, Phe-195, Leu-191 and Leu-75, form the narrowest part of the pore. Therefore water molecules are not expected to transport through the central pore, which was confirmed by MD simulations. Each monomer of the AQP4 tetramers forms a channel whose walls consist mostly of hydrophilic residues. There are eight water molecules in single file observed in each of the four channels, transporting through the selectivity filter containing Arg-216, His-201, Phe-77, Ala-210, and the two conserved Asn-Pro-Ala (NPA) motifs containing Asn-213 and Asn-97. By using Brownian dynamics fluctuation-dissipation-theorem (BD-FDT), the overall free-energy profile was obtained for water transporting through AQP4 for the first time, which gives a complete map of the entire channel of water permeation.
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Project description:The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage.
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Project description:Transgenic null mice were used to test the hypothesis that water channel aquaporin-4 (AQP4) is involved in colon water transport and fecal dehydration. AQP4 was immunolocalized to the basolateral membrane of colonic surface epithelium of wild-type (+/+) mice and was absent in AQP4 null (-/-) mice. The transepithelial osmotic water permeability coefficient (P(f)) of in vivo perfused colon of +/+ mice, measured using the volume marker (14)C-labeled polyethylene glycol, was 0.016 +/- 0.002 cm/s. P(f) of proximal colon was greater than that of distal colon (0.020 +/- 0.004 vs. 0. 009 +/- 0.003 cm/s, P < 0.01). P(f) was significantly lower in -/- mice when measured in full-length colon (0.009 +/- 0.002 cm/s, P < 0. 05) and proximal colon (0.013 +/- 0.002 cm/s, P < 0.05) but not in distal colon. There was no difference in water content of cecal stool from +/+ vs. -/- mice (0.80 +/- 0.01 vs. 0.81 +/- 0.01), but there was a slightly higher water content in defecated stool from -/- mice (0.68 +/- 0.01 vs. 0.65 +/- 0.01, P < 0.05). Despite the differences in water permeability with AQP4 deletion, theophylline-induced secretion was not impaired (50 +/- 9 vs. 51 +/- 8 microl. min(-1). g(-1)). These results provide evidence that transcellular water transport through AQP4 water channels in colonic epithelium facilitates transepithelial osmotic water permeability but has little or no effect on colonic fluid secretion or fecal dehydration.
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Project description:Alzheimer's disease (AD) is a misfolded protein disease characterized by the accumulation of ?-amyloid (A?) peptide as senile plaques, progressive neurodegeneration, and memory loss. Recent evidence suggests that AD pathology is linked to the destabilization of cellular ionic homeostasis mediated by toxic pores made of A? peptides. Understanding the exact nature by which these pores conduct electrical and molecular signals could aid in identifying potential therapeutic targets for the prevention and treatment of AD. Here using atomic force microscopy (AFM) and molecular dynamics (MD) simulations, we compared the imaged pore structures with models to predict channel conformations as a function of amino acid sequence. Site-specific amino acid (AA) substitutions in the wild-type A?(1-42) peptide yield information regarding the location and significance of individual AA residues to its characteristic structure-activity relationship. We selected two AAs that our MD simulation predicted to inhibit or permit pore conductance. The substitution of Phe19 with Pro has previously been shown to eliminate conductance in the planar lipid bilayer system. Our MD simulations predict a channel-like shape with a collapsed pore, which is supported by the AFM channel images. We suggest that proline, a known ?-sheet breaker, creates a kink in the center of the pore and prevents conductance via blockage. This residue may be a viable target for drug development studies aiming to inhibit A? from inducing ionic destabilization toxicity. The substitution of Phe20 with Cys exhibits pore structures indistinguishable from the wild type in AFM images. MD simulations predict site 20 to face the solvated pore. Overall, the mutations support the previously predicted ?-sheet-based channel structure.
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Project description:Aquaporins (AQPs) facilitate the passive flux of water across biological membranes in response to an osmotic pressure. A number of AQPs, for instance in plants and yeast, have been proposed to be regulated by phosphorylation, cation concentration, pH change, or membrane-mediated mechanical stress. Here we report an extensive set of molecular dynamics simulations of AQP1 and AQP4 subject to large membrane potentials in the range of ±1.5 V, suggesting that AQPs may in addition be regulated by an electrostatic potential. As the regulatory mechanism we identified the relative population of two different states of the conserved arginine in the aromatic/arginine constriction region. A positive membrane potential was found to stabilize the arginine in an up-state, which allows rapid water flux, whereas a negative potential favors a down-state, which reduces the single-channel water permeability.
| S-EPMC3000486 | biostudies-literature
Project description:Aquaporins (AQPs) are protein channels located across the cell membrane which conduct the water permeation through the cell membrane. Different types of AQPs exist in human organs and play vital roles, as the malfunction of such protein membranes can lead to life-threatening conditions. A specific type of AQP, identified as AQP5, is particularly essential to the generation of saliva, tears and pulmonary secretions. We have adopted Molecular Dynamics (MD) simulation to analyze the water permeation and diffusion in AQP5 structure in a 0.5 microsecond simulation time window. The MD numerical simulation shows the water permeability of the human AQP5 is in the nominal range for other members of human aquaporins family. In addition, we have considered the effect of the osmotic water diffusion and the diffusion occurred by pressure gradient on the protein membrane. The water permeability grows monotonically as the applied pressure on the solvent increases. Furthermore, the forced diffusion increases the minimum radius of Selectivity Filter (SF) region of region AQP5 up to 20% and consequently the permeability coefficients enhance enormously compared to osmotic self-diffusion in AQP5 tetramer. Finally, it is revealed that the MD simulation of human AQP5 provides useful insights into the mechanisms of water regulation through alveolar cells under the different physical conditions; osmotic self-diffusion and forced diffusion condition.
| S-EPMC6353642 | biostudies-literature
Project description:Aquaporin (AQP) functions as a water-conducting pore. Mercury inhibits the water permeation through AQP. Although site-directed mutagenesis has shown that mercury binds to Cys189 during the inhibition process, it is not fully understood how this inhibits the water permeation through AQP1. We carried out 40 ns molecular dynamics simulations of bovine AQP1 tetramer with mercury (Hg-AQP1) or without mercury (Free AQP1). In Hg-AQP1, Cys191 (Cys189 in human AQP1) is converted to Cys-SHg+ in each monomer. During each last 10 ns, we observed water permeation events occurred 23 times in Free AQP1 and never in Hg-AQP1. Mercury binding did not influence the whole structure, but did induce a collapse in the orientation of several residues at the ar/R region. In Free AQP1, backbone oxygen atoms of Gly190, Cys191, and Gly192 lined, and were oriented to, the surface of the water pore channel. In Hg-AQP1, however, the SHg+ of Cys191-SHg+ was oriented toward the outside of the water pore. As a result, the backbone oxygen atoms of Gly190, Cys191, and Gly192 became disorganized and the ar/R region collapsed, thereby obstructing the permeation of water. We suggest that mercury disrupts the water pore of AQP1 through local conformational changes in the ar/R region.
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Project description:Aquaporin-3 (AQP3) is a water channel expressed at the basolateral plasma membrane of kidney collecting-duct epithelial cells. The mouse AQP3 cDNA was isolated and encodes a 292-amino acid water/glycerol-transporting glycoprotein expressed in kidney, large airways, eye, urinary bladder, skin, and gastrointestinal tract. The mouse AQP3 gene was analyzed, and AQP3 null mice were generated by targeted gene disruption. The growth and phenotype of AQP3 null mice were grossly normal except for polyuria. AQP3 deletion had little effect on AQP1 or AQP4 protein expression but decreased AQP2 protein expression particularly in renal cortex. Fluid consumption in AQP3 null mice was more than 10-fold greater than that in wild-type litter mates, and urine osmolality (<275 milliosmol) was much lower than in wild-type mice (>1,200 milliosmol). After 1-desamino-8-d-arginine-vasopressin administration or water deprivation, the AQP3 null mice were able to concentrate their urine partially to approximately 30% of that in wild-type mice. Osmotic water permeability of cortical collecting-duct basolateral membrane, measured by a spatial filtering optics method, was >3-fold reduced by AQP3 deletion. To test the hypothesis that the residual concentrating ability of AQP3 null mice was due to the inner medullary collecting-duct water channel AQP4, AQP3/AQP4 double-knockout mice were generated. The double-knockout mice had greater impairment of urinary-concentrating ability than did the AQP3 single-knockout mice. Our findings establish a form of nephrogenic diabetes insipidus produced by impaired water permeability in collecting-duct basolateral membrane. Basolateral membrane aquaporins may thus provide blood-accessible targets for drug discovery of aquaretic inhibitors.
| S-EPMC18251 | biostudies-literature
Project description:Water permeation and electrostatic interactions between water and channel are investigated in the Escherichia coli glycerol uptake facilitator GlpF, a member of the aquaporin water channel family, by molecular dynamics simulations. A tetrameric model of the channel embedded in a 16:0/18:1c9-palmitoyloleylphosphatidylethanolamine membrane was used for the simulations. During the simulations, water molecules pass through the channel in single file. The movement of the single file water molecules through the channel is concerted, and we show that it can be described by a continuous-time random-walk model. The integrity of the single file remains intact during the permeation, indicating that a disrupted water chain is unlikely to be the mechanism of proton exclusion in aquaporins. Specific hydrogen bonds between permeating water and protein at the channel center (at two conserved Asp-Pro-Ala "NPA" motifs), together with the protein electrostatic fields enforce a bipolar water configuration inside the channel with dipole inversion at the NPA motifs. At the NPA motifs water-protein electrostatic interactions facilitate this inversion. Furthermore, water-water electrostatic interactions are in all regions inside the channel stronger than water-protein interactions, except near a conserved, positively charged Arg residue. We find that variations of the protein electrostatic field through the channel, owing to preserved structural features, completely explain the bipolar orientation of water. This orientation persists despite water translocation in single file and blocks proton transport. Furthermore, we find that for permeation of a cation, ion-protein electrostatic interactions are more unfavorable at the conserved NPA motifs than at the conserved Arg, suggesting that the major barrier against proton transport in aquaporins is faced at the NPA motifs.
| S-EPMC1303569 | biostudies-literature