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Department of Biochemistry, Center for Biophysics and Computational Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
* To whom correspondence should be addressed. E-mail: emad{at}life.uiuc.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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Transport of materials across biological membranes is a fundamental process in all living cells. Small, uncharged molecules, such as alcohols and gas molecules, can readily traverse lipid bilayers. Charged and polar molecules, however, require special pathways to cross the cellular membrane, as the hydrophobic tails of lipid molecules create a considerable energetic barrier against their diffusion. Membrane channels provide such pathways for selective exchange of water-soluble materials, e.g. water, ions, and other nutrients, across the membrane. Three major functional characteristics of membrane channels, which are furnished by specific arrangements of amino acids in their structure, are permeation, selectivity, and gating. Recent developments in experimental structural biology and computer simulation methodologies have advanced our understanding of the mechanisms and the bases of these functional aspects in membrane channels at atomic resolution.
Water constitutes 
70% of the mass of most living organisms. Regulation of water flow across cell membranes is critical for maintaining proper fluid balance within the cell and within different anatomic compartments. Permeation of water across cellular membranes is facilitated by a family of membrane channels called aquaporins (AQP)4 (1–4). These selective channels are present in all forms of life, including mammals, amphibia, insects, plants, and bacteria (2–4). In humans, 13 different AQP (AQP0–AQP12) have been characterized in various organs, e.g. kidneys, eyes, and the brain.
Although generally known for endowing a high transmembrane permeability to water (5,6), involvement of AQP in a variety of other cellular processes has also been reported (3,7–9), e.g. permeation of small molecules other than water (10), gas conduction (11–14), and even cell-cell communication (15). The physiological importance of AQP is reflected in many common pathophysiological situations associated with their absence and/or impaired function (2,3,8,9,16). Research on knockout mice has shown that active fluid transport in proximal tubules and salivary glands is seriously compromised by AQP deletion (17). Impaired functions of AQP0 and AQP2 have been directly linked to cataracts and diabetes insipidus, respectively (2,3,16,18). Recent studies on AQP4, the predominant AQP in the central nervous system, have related its loss from perivascular membranes with ischemic brain injury (19,20). Pharmacological modulation of AQP4 function may provide a novel therapeutic strategy for disorders of the central nervous system (21). Other diseases linked to AQP include Sjögren's syndrome and impaired hearing (2,16,22).
AQP present the richest family of membrane channels with regard to the abundance of high resolution structural data. Three-dimensional crystallographic structures of several members of the family have been solved. The structures of 2 bacterial AQP [GlpF, a glycerol channel (23,24), and AqpZ (25), an orthodox water channel] and 5 mammalian AQP [human AQP1 (26), bovine AQP1 (27), rat AQP4 (28), as well as bovine and sheep AQP0 at 2 different pH conditions (29–31)] are available at full atomic resolution. Most recently, 2 new AQP structures have been reported: the structure of AqpM, an archaeal H2S channel (32), and the structures of a plant AQP (spinach PIP2) in both closed- and open-gated states (33). The solved structures of several AQP at high resolution are indicative of a conserved protein architecture in the whole family. All members of the family form homotetramers in the membrane (Fig. 1) in which 4 functionally independent pores provide highly selective, yet efficient, pathways for water permeation across the low dielectric barrier of lipid bilayers. Another pore, known as the central pore, is formed between the 4 monomers.
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Early simulation studies on AQP focused on the structural stability of the channel and investigated the mechanism and dynamics of substrate permeation. The resolution of the available X-ray structures turned out to be very important in calculating accurate permeation rates for water in these channels. Simulations of AQP1 in a membrane using a lower resolution structure (3.8 Å) of the channel found the conformation of critical amino acids lining the pore to be unstable and, thus, failed to correctly describe the permeation speed (34).
Water permeation through most AQP is very fast and can be observed on nanosecond time scales in MD simulations under equilibrium conditions; for instance, multiple permeation events of water molecules from one side of the membrane to the other have been observed in, e.g., AQP1 and GlpF under equilibrium conditions (24,54). The size of the pore in AQP is not large enough to accommodate more than a single water molecule in most regions along the channel axis. As such, water is conducted in a single file configuration (Fig. 2) in which the motion of water molecules are highly correlated (40). The single file configuration of water proved extremely important in the selectivity mechanisms employed by the channel (24).
Although such simulations allow one to calculate equilibrium properties of water channels, most experimental results for water permeation through AQP have been obtained under osmotic pressure conditions, i.e. nonequilibrium conditions. To simulate the channel under similar conditions, a novel computational method was developed (41,55). The method takes advantage of applying small forces to bulk water molecules to generate a hydrostatic pressure gradient across the membrane, thus changing the chemical potential of water on the 2 sides of the membrane. Under such conditions, net flow of water across the membrane is observed. Using this method, the pressure difference between the 2 sides of the membrane can be readily changed. Applying different pressure gradients, the osmotic permeability of GlpF (55) and AQP1 (41) has been calculated and found to be in good agreement with experimental values.
Simulation of glycerol saturated models of GlpF, as reported in the crystal structure (23), resulted in a qualitative description of the substrate pathway (35). A more quantitative picture of the event was provided by pulling glycerol through the channel and calculating the associated free energy profile (36). Simulations of GlpF in membrane (Fig. 1) succeeded in simulating diffusive water permeation through these channels, but also paid more attention to the mechanism of proton blocking in these channels and proposed a unique configuration of water molecules (Fig. 2) as a novel mechanism of proton exclusion (24). Further computational studies using different methodologies elaborated on the details of the proposed mechanism (40,42,49,51,56).
Membrane insertion of AQP
Like other membrane proteins, for a proper function, AQP need to be inserted into the cellular membrane. The structure of a folded membrane protein, hydrophobic properties of its surface, as well as the arrangement of certain aromatic residues at the surface of the protein are critical for this process. Generally, a membrane protein exhibits a large hydrophobic surface formed by nonpolar residues where the protein interfaces with the hydrophobic core of the lipid bilayer (see Fig. 3 for an example). Interestingly, aromatic amino acids, particularly tyrosine (Tyr) and tryptophan (Trp), are found frequently at the interface of the hydrophobic core and the head group region of lipid bilayers. This is most likely due to their chemical heterogeneity, namely possessing both hydrophobic properties and the ability of forming hydrogen bonds, which makes them ideal for interfacial regions where a residue is in contact with both hydrophobic and polar environments (57–60).
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Substrate selectivity
Along with the discovery of novel functions for AQP and the availability of more structures for the members of the family, we have begun to understand the physical mechanisms of specific functions of these channels. AQP are divided into 2 subfamilies, orthodox AQP, which only conduct water, and aquaglyceroporins, which have the additional ability of conducting other small molecules, such as glycerol (61,62), urea (3), nitrate (63), and arsenite (64). Although most conducted molecules are neutral, there may be exceptions in which AQP have been suggested to conduct charged species, in particular ions. For example, AQP6, a mammalian AQP, can act as a chloride channel (65,66). Also, it has been shown that AQP1 can be activated by cyclic guanosine monophosphate (cGMP) to conduct cations in a nonselective manner (46,67). Given the very similar architecture and overall structures of AQP, it is of great interest to understand what subtle differences in their amino acid composition and structure are responsible for their different conduction properties.
In Escherichia coli, 2 different AQP have been characterized: AqpZ, a pure water channel, and GlpF, an aquaglyceroporin that conducts glycerol along with water. The availability of high-resolution structures of these 2 structurally highly homologous, but functionally distinct, AQP from the same species presented us with a unique opportunity to develop an understanding of the structural basis underlying substrate selectivity in these channels (44). Despite the very similar structures, the conduction properties of these 2 channels are quite different. The difference has been attributed to various structural elements, namely the size of the pore and the nature of amino acids composing the so-called selectivity filter (SF), i.e. the narrowest spot of the pore located very close to the periplasmic vestibule of the channel (25,44,68).
The amino acid composition and the structure of the SF of GlpF and AqpZ are compared in Figure 4. As shown, aromatic amino acids are major constituents of the SF. In the case of the glycerol channel GlpF, the SF is composed of a hydrophobic wedge [Trp and phenylalanine (Phe)] on one side and a hydrophilic face [arginine (Arg)] on the opposite side. The hydrophobic wedge formed by the aromatic amino acids (conserved in the members of the aquaglyceroporin subfamily) provides a greasy slide for glycerol and other linear sugar molecules conducted by the channel and thus may play an important role in selectivity for glycerol (23). In AqpZ, as well as other orthodox AQP, the SF exhibits a very different composition, resulting in an increased polarity of the channel in this region. The aromatic side chains of Trp and Phe in GlpF are now replaced by a Phe and histidine, respectively (Fig. 4). Glycerol channels present an example in which aromatic amino acids play an important role in defining both the size and the polarity of functionally critical regions in a protein.
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3 times larger in AqpZ than in GlpF (36) in the SF region, clearly in line with the known permeabilities of these 2 channels. However, the results indicated that a high barrier against glycerol permeation arose not only in the SF region of AqpZ, which is believed to account for the main structural difference between AqpZ and GlpF, but along the entire channel. In agreement with the energetics, calculation on the pore size of the 2 AQP found an overall narrower pore in AqpZ (Fig. 4) (44). The results suggest that the difference in substrate selectivities of AqpZ and GlpF may not be simply due to only those residues that directly line the channel (44), i.e. the smaller pore size along the whole AqpZ channel cannot be explained only by implicating channel-lining residues (44). To convert a water channel into a glycerol channel, one must identify remote residues that do not directly interact with the permeant but nevertheless control the channel diameter through shifting and tilting helices forming the pore (44).
Gating of water pores and the central pore
Most AQP are believed to operate as permanently open water channels. However, gating of water pores has been reported for a large number of AQP, particularly for, but not limited to, plant AQP (Fig. 5). Obviously, regulating water permeability of AQP is critical for the control of water flow into and out of the cell. For instance, plants respond to drought or flood conditions by shutting down almost all of their AQP. Common signals through which water pores are gated include changes in environmental pH and phosphorylation (29,33,70,71). pH- and phosphorylation-mediated gating have also been reported for mammalian AQP, such as AQP0 (29,70) and AQP4 (72). Solving the structure of AQP0 under 2 different pH conditions was an attempt to shed light on the structural elements involved in pH gating. However, as the 2 structures were found to be almost identical, the mechanism of pH gating seems to be more complex than expected (29,30).
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We also examined ion permeation through the putative central pore by pulling a sodium ion through the pore and by constraining the ion at different regions along the pore axis (46). Simulations allowed us to identify major barriers against ion permeation through the central pore. Protein conformational changes and/or pore hydration in response to the presence of the ion were analyzed. The most marked effects were considerable hydration of the pore and large conformational changes of loop D (46).
Furthermore, the effect of cGMP binding on the protein was studied by simulations in which 4 cGMP molecules were placed on the surface of the protein. During the simulation, cGMP molecules established multiple contacts with loop D (46). The conformation of this flexible loop was highly perturbed by cGMP, mainly through strong interactions of the nucleotide with an Arg-rich region of the loop. Retraction of the D loops of the 4 monomers away from the central pore not only physically unblocked the entrance of the central pore but also resulted in conformational changes of a ring of pore-lining, hydrophobic residues that formed a gate and block the access of water (Fig. 6). The helix bearing these hydrophobic residues was immediately connected to loop D and it was very likely that the conformational coupling of loop D and this helix was the molecular mechanism of detecting cGMP binding inside the central pore (46). The involvement of Arg in the gating mechanism was successfully verified by experimental measurements on a double mutant species in which 2 of the Arg had been knocked out (46). The mutant exhibited a water permeability very similar to that of the wild type, while its ion conductivity was almost completely abolished (46). Based on the results of our simulations, a gating mechanism has been proposed in which loop D plays a critical role in controlling the accessibility of the central pore to water and hydrated ions (46).
The similarity between the gating mechanism proposed for cGMP activation of the central pore of AQP1 (46) and phosphorylation-induced gating of water pores in spinach PIP2 (33) is striking. In both cases, the conformation of the same cytoplasmic loop (loop D) controls the position of hydrophobic residues that directly line the pore and can very effectively open or close the pore.
Gas permeation through AQP
AQP conduct O2 and CO2 across biological membranes (12–14,75–80). Due to the usually high density of AQP in cellular membranes, physiological relevance of gas permeation through AQP has been strongly suspected. To shed light on the mechanism and pathway of gas conduction, the permeability of mammalian AQP1 to O2 and CO2 was investigated using 2 complementary simulation methodologies (80) applied to both membrane-embedded models of tetrameric AQP1 as well as to pure lipid bilayer models. The simulations showed that the central pore of AQP1 can be readily used by either gas molecule to permeate the channel (Fig. 6). A major energy barrier is identified only in the periplasmic vestibule and appears to be mainly due to a dense cluster of water molecules anchored in the periplasmic mouth of the central pore by specific aspartate residues.
The monomeric water pores of AQP1 were found to be less gas permeable than the central pore, likely due to the strong hydrogen bonds between the protein and water molecules inside the channel. Water pores show a very low permeability to O2 but may contribute to the overall permeation of CO2 due to its more hydrophilic nature. Although the central pore of AQP1 is found to be gas permeable, a pure palmitoyloleyl-phosphatidylethanolamine bilayer provides a much larger cross-sectional area, thus exhibiting a much lower energy barrier for CO2 and O2 permeation.
Our simulations suggest that, aside from its conventional role as the water channel, AQP1 might provide a pathway for small, neutral gas molecules across the membrane. However, compared with a pure palmitoyloleyl-phosphatidylethanolamine bilayer with a similar area, AQP1 is less gas permeable to both CO2 and O2. Therefore, gas conduction through AQP1 may be of physiological importance only in membranes with low intrinsic gas permeability or where a major fraction of the surface area of the membrane is occupied by AQP.
We found that both CO2 and O2 entered the AQP1 central pore spontaneously and observed 1 full permeation event for each type of gas molecule. We found 8 CO2 and 5 O2 molecules inside the central pore of AQP1 as the equilibrium simulations ended at 30 ns and 26 ns, respectively (Fig. 6). Our results suggest that the hydrophobic central pore of AQP1 is indeed permeable to both CO2 and O2. Our gas diffusion simulations further revealed a full permeation event of each type of gas molecule through the central pore. Compared with the well-characterized water pores, the central pore of AQP is poorly understood and it remains a long-standing question whether it has any physiological importance. Our simulations suggest that the AQP1 central pore provides a potential pathway for gas permeation and that this pathway can play a physiological role either in membranes with low intrinsic gas permeabilities or when a major fraction of the membrane is occupied by AQP.
Selectivity, permeation, and gating mechanisms are the 3 functional properties that characterize channel proteins. Because of the wealth of structural information and the simplicity of their basic function, AQP have served as ideal membrane channels for structure-function relation studies. The large number of structurally known AQP complemented by numerous computational studies performed on different members of the family have provided an unparalleled level of detail regarding the mechanisms of permeation, selectivity, and gating of these channels. Despite the wealth of structural information available for AQP, we have just begun to understand structural determinants and principles of substrate permeation and selectivity in these channels (25,44). So far, almost all mutagenesis studies attempting to interconvert water and glycerol channels have failed, indicating that the mechanism of substrate selectivity of monomeric pores in AQP is only poorly understood. Our knowledge of the function of the central pore is even more scarce. There are only a handful of reports in the literature implicating the central pore in conduction of permeants other than water under certain circumstances (67,73). It is, therefore, of great importance and physiological relevance to investigate the underlying selectivity of these channels for various substrates at an atomic level.
Permeation of water, glycerol, ions, and gas molecules through the monomeric water pores and the central pore in AQP have been successfully simulated by MD simulations. These studies have revealed selectivity mechanisms that could not be identified otherwise. Future computational studies will focus more on the subject of selectivity and might result in designed mutants with altered permeation and selectivity properties.
In contrast to the water pores, the role of the central pore in AQP is very poorly understood; AQP monomers function completely independently but are found almost invariably in tetramers, a property that strongly suggests a physiological role for the central pore. Future biochemical assays and computational work can shed more light on the unknown role of the central pore in AQP. Simulation studies have also contributed to our understanding of the mechanisms of gating of water pores and the central pore in AQP.
Despite the important strides taken in experimental and computational structural studies of AQP, they present a young field of research. The function and physiological role of AQP in many tissues and organs are unclear. More biological studies applying more sensitive and novel biochemical and biophysical assays are needed to identify the many facets of the function of these channels, and we should expect to see many functions for AQP other than pure innocent water channels.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by grants from NIH (P41-RR05969 and R01-GM067887).
3 Author disclosures: E. Tajkhorshid, Ajinomoto Company Inc. provided the travel expense to attend the meeting; Yi Wang, no conflicts of interest.
4 Abbreviations used: AQP, aquaporin; Arg, arginine; cGMP, cyclic guanosine monophosphate; MD, molecular dynamics; Phe, phenylalanine; SF, selectivity filter; Trp, tryptophan; Tyr, tyrosine.
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