“Sticky”-Ends-Guided Creation of Functional Hollow Nanopores for

Apr 13, 2016 - To our delight, these aquapores demonstrate their excellent ability of highly selectively hosting a chain of single file H-bonded water...
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“Sticky”-Ends-Guided Creation of Functional Hollow Nanopores for Guest Encapsulation and Water Transport Yanping Huo† and Huaqiang Zeng*,‡ †

Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, Guangdong 510006, China Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669

‡

CONSPECTUS: Commercial uses of water-transporting aquaporins for seawater desalination and wastewater reclamation/reuse are being investigated in both academia and the industry. Presently, structural complexity, stability, scalability, and activity reconstitution of these costly channel proteins still present substantial challenges to scientists and engineers. An attractive strategy is to develop robust synthetic water channels able to mimic the water-transporting function of aquaporins for utility in the making of next generation of water channelbased biomimetic porous membranes for various water purification applications. In sharp contrast to burgeoning development in constructing synthetic ion channels over the past four decades, very limited progress has been made in the area of synthetic water channels. A handful of such examples include the first report by Percec in 2007 (Percec et al. J. Am. Chem. Soc. 2007, 129, 11698−11699), which was followed by Barboiu in 2011 (Barboiu et al. Angew. Chem., Int. Ed. 2011, 50, 11366− 11372), Gong and Hou in 2012 (Gong et al. Nat. Commun. 2012, 3, 949; Hou et al. J. Am. Chem. Soc. 2012, 134, 8384−8387), and Zeng in 2014 (Zeng et al. J. Am. Chem. Soc. 2014, 136, 14270−14276). Radically deviating from the fact that the discovery of novel synthetic channel systems with desired transport selectivity is most often empirical and very often serendipitous, we have instead adopted a more rational designer approach whereby molecular building blocks have been carefully designed from scratch to perform their intended built-in functions. Our designer journey started in 2008, two years after I started leading a group at the National University of Singapore. Since then, we have been actively investigating the use of designed water-binding “aquafoldamers” to construct synthetic water channels for the rapid and selective transport of water molecules ideally with the exclusion of all other nonproton molecular species. Toward this goal, we designed and characterized, by an experimental-theoretical synergy, a new class of modular, H-bonded, and crescent-shaped oligopyridine amide foldamers, enclosing a sizable cavity of about 2.8 Å in diameter. Matching well with the diameter of water molecules and decorated by interior-pointing H-bond donors (amide H atoms) and acceptors (pyridine N atoms) for water binding, this sizable cavity experimentally proves to be suitable for water recognition. In particular, helically folded oligomers are found to be capable of binding two water molecules that are vertically aligned in parallel with helical axis. However, the existence of two repulsive groups at the two helical ends prevents the formation of 1D hollow tubular cavity, via self-assembly, for encapsulating 1D water chains. Subsequently, we introduced two electrostatically complementary functional groups that act as “sticky” ends at helical ends. These feeble “sticky” ends faithfully and seamlessly align short cavity-containing helices onedimensionally to create hollow tubular aquapores. To our delight, these aquapores demonstrate their excellent ability of highly selectively hosting a chain of single file H-bonded water molecules and allow for selective transport of both protons and water molecules with exclusion of metal ions including Na+ and K+ ions across the lipid membranes.

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INTRODUCTION

enthusiastic Nature’s followers in imitating the structure and function of the one-dimensional (1D) tubular hollow nanopores, a key central component present in all transmembrane protein channels. Over the past three decades, these synthetic attempts have culminated in various strategies that employ diverse molecular building blocks to create synthetic speciestransporting channels,1−15 which also offer many other additional prospects in applications such as separation, sensing,

Maintaining concentration gradients of ions, water, and other nutrients between intra- and extracellular regions is crucial for the cell to survive and to perform complex and exquisite cellular functions. Protein channels, a class of specialized membrane proteins, are Nature’s most utilized evolutionary choice for preserving such an unsymmetrical environment whereby varied nutrients, particularly ions, are tightly regulated at the most optimized level for cellular needs. Challenged by the sheer complexity of structure in these natural protein channels, a synthetic minimalist approach has been adopted extensively by © XXXX American Chemical Society

Received: January 30, 2016

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Figure 1. Folding molecules derived from (a,b) methoxybenzene, (c) pyridone, (d) fluorobenzene, and (e) pyridine units. Crystal structures of 1−4 and computationally determined structure of 5 are shown below the chemical structures. For clarity of view, the interior methyl groups in 1 and 2 were removed, and those isobutyl groups in 3 were replaced by dummy yellow atoms.

drug delivery, and catalysis.16−22 Among many advances in artificial channel systems, channels for ion transport received the most attention,1−11 with much less progress being made in the area of synthetic water channels.13−15 Limited examples were recently reported by Percec in 2007,23 Barboiu in 2011,24 Gong25 and Hou26 in 2012, and our group in 2014.27 Naturally occurring aquaporins are protein-based water channels through which water molecules move rapidly at a rate of 109 molecules per second across the cell membrane with the passage of protons and ions strictly prevented.28 These remarkable properties have inspired both academia and industry to explore commercial uses of aquaporins-based biomimetic membranes for seawater desalination and wastewater reclamation/reuse.29,30 Presently, structural complexity, stability, scalability, and activity reconstitution of these costly channel proteins still present substantial challenges to scientists and engineers, greatly limiting the performance of these biomimetic membranes. An alternative strategy to alleviate these challenges is to develop completely synthetic water channels that could enable selective water transport across the membrane. Complete artificiality may endow these channel molecules with better stability, mechanical strength, and scalability than protein counterparts, thus allowing simpler membrane fabrication and system integration. Detailed analyses of the crystal structures of aquaporins31,32 reveal a fourfold structural basis for concurrently promoting high water permeability and high salt rejection: (1) alignment of water molecules in single file over a 20 Å trim span, (2) a central pore opening of ∼2.8 Å in diameterjust big enough for a single water molecule, (3) a fixed positive charge from the central arginine side chain for repelling protons, and (4) two conserved asparagines in channel center that prevent the formation of a “proton” wire but allow water to move via transiently formed H-bonds with no resistance. Such an evolutionarily advanced design in structure and function makes it exceptionally challenging to simultaneously recapit-

ulate aquaporin’s essential structural features and startling functions. It is therefore very meaningful for a completely abiotic system to imitate the protein’s key structural traits and functions using a minimalist approach. In this Account, we review our recently elaborated designer strategy toward building up aquafoldamer-based artificial water channels from scratch, selectively recapturing the aquaporin’s key feature of having a narrow pore constriction of 2.8 Å, its ability to one-dimensionally align water molecules, and its water-transporting function with high salt rejection.27,33−38

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COMPUTATIONAL DE NOVO DESIGN OF WATER-BINDING AQUAFOLDAMERS33,34 For seawater desalination, the ions of main concern include Na+ (10.75 g/L), Mg2+ (1.30 g/L), Ca2+ (0.42 g/L), K+ (0.39 g/L), Cl− (19.35 g/L), SO42− (2.70 g/L), and HCO3− (0.15 g/ L). Compared to a water molecule having a diameter of ∼2.8 Å, these hydrated metal ions containing six coordinated water molecules are much larger and roughly measure 7.2 Å for Mg2+, 7.9 Å for Na+ and Ca2+, and 8.6 Å for K+ with hydrated anions even larger. Given this large difference in size between the hydrated ions and a water molecule, we envisioned that a hollow tubular nanopore, which is sufficiently small in diameter and further lacks binding elements for liberating ions from their hydration shell, might selectively transport water molecules in the presence of ions or larger molecular species. Furthermore, preventing proton transport across the pore seems to be irrelevant within the context of seawater desalination or wastewater reclamation. For these reasons, as well as facile synthetic accessibility, we focus our attention on molecules that are simple but able to generate a stable aquapore preferring water over nonproton molecular species. Applying an inner design strategy,39 we recently demonstrated that an internally placed continuous H-bonding network can be used to effectively induce helically40 or circularly41−44 folded conformations in aromatic amide foldamers. These B

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Accounts of Chemical Research folding molecules are derived from methoxybenzene (1 and 2),40−42 pyridone (3),43 or fluorobenzene (4)44 units that help to enclose a cavity of ∼2.8 Å across after excluding van der Waals volume of O- or F atoms (Figure 1a−d). Despite having a desired cavity size for water recognition, these cavities originally designed for incorporation into unimolecular ion channels were decorated by hydrophilic cation-binding elements able to bind metal ions more strongly than water molecules.43,45−47 In 2008, we also became interested in anion and water channels. Equipped with rich knowledge in structure, cavity size, and ion-binding function of these helical or circular aromatic foldamers, we anticipated that the use of pyridinebased repeating units might allow these hydrophilic cavities to be modified into somewhat more hydrophobic one, possessing an increased cavity size of about 4 Å in diameter (5, Figure 1e). The resultant cavity in 5, which contains five interiorly arrayed amide H atoms as H-bond donors, might display good affinities toward halide anions ranging from 2.38 Å (F−) to 4.12 Å (I−) in diameter, or a water molecule of 2.8 Å in diameter, but not alkaline metal ions. As envisaged, a computational treatment at the B3LYP/631G(d,p) level in gas phase unveils a considerably enlarged cavity in 5 (Figure 1e) than those contained in 2−4. Unexpectedly, however, the optimized macrocyclic backbone in 5 turns out to be highly distorted, instead of roughly planar seen in 2−4. This significant deviation from macrocyclic planarity made us realize that the pyridine-based asymmetric bifunctional unit in 5 might induce a larger backbone curvature than methoxybenzene, pyridone, or fluorobenzene units. Subsequent closer analyses of the computationally optmized acyclic oligomers, for example, trimer 6, tetramer 7, and pentamer 8 establish an average of 84° turn in helical backbone induced by every pyridine-based repeating unit. Accordingly, instead of five repeating units per helical turn as in 1−4, 4.3 units are sufficient to complete a helical turn, enclosing a helical cavity of 2.8 Å across (Figure 2a−c). Circular tetramer 9, having a perfectly planar backbone and containing a smaller cavity of 2.3 Å, can only accommodate a fluoride anion with other larger halide anions staying above the planar cavity (Figure 2d). Futher computational treatments reveal a nice fit of one water molecule into the planar or near-planar cavities contained in 6 and 7 and water dimer into the 3D-shaped helical cavity in 8. In these water complexes, water molecules are primarly stabilized by two or three strong intermolecular Hbonds of ≤2.1 Å and additionally by weak H-bonds or VDW forces, producing overall interaction energies of 7.81, 10.27, and 14.22 kcal/mol for 6·H2O, 7·H2O, and 8·2H2O, respectively.

Figure 2. Structures of 6−9 and their water or halide complexes computationally optimized at the B3LYP/6-31G(d,p) level in gas phase.

and Cbz groups at two helical ends, becomes 3D-shaped, and pentamer 13 is clearly helically folded. In 13a, each repeating unit induces on average a turn of ∼83° and hence 4.3 pyridinebased units are required in order to achieve a complete helical turn, values that are remarkably identical to the computationally determined ones. Since interatomic distances between adjacent amide protons, and between end ester and Cbz groups fall within 5 Å in the solid state, 2D NOESY experiments were carried out to probe if the crescently shaped or helically foled conformations also persist in solution for 11−13. In accordance with the crescent conformation adopted by 11 in solution, NOESY study at 263 K reveals both NOE cross peaks among amide protons and end-to-end NOE contacts between end methoxy protons a and Cbz protons g Similarly, the observed end-to-end NOE contacts between protons a and g for 12 and between protons a4 and g for 13a (Figure 3e) are consistent with their respective interatomic distances of 2.83 and 4.43 Å in the solid state, and unambiguously confirmes a helically folded highly curved structure taken by both 12 and 13a in solution.

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AQUAFOLDAMERS’ HIGHLY CURVED STRUCTURES33 Perplexed by the contradictory computational finding on the greater backbone curvature dictated by pyridine-based folding units in 5−9 than those found in 1−4, we decided to prepare a series of acyclic pyridine oligoamides ranging from dimer 10 to pentamer 13 in order to experimentally examine their true backbone curvatures (Figure 3). The determined crystal structures of 10−13a comprising H-bonded progessively lengthened backbones indeed demonstrate increasingly curved aromatic backbones efficiently rigidified by increasingly gained stabilizing H-bonding forces consisting of up to nine intramolecular H-bonds (pyridine N···H of amide groups = 2.10− 2.39 Å). In other words, whereas shorter oligomers 10 and 11a are roughly planar, tetramer 12, having sterically hindered ester C

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Figure 3. Crystal structures of 10−13a (a−d). (e) illustrates end-to-end NOE contacts in CDCl3 for 12 and 13a with their correspondng shortest interatomic distances d(Ha−Hg) and d(Ha4−Hg) in the solid state. NOE contact was also seen between protons a and g (d(Ha−Hg) = 3.44 Å) for 11a.

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AQUAFOLDAMERS’ WATER-BINDING FUNCTIONS34,35

Elucidated computationally and crystallographically, the Hbond-enforced aromatic backbones in 11-13 enclose an internal cavity of ∼2.8 Å in diameter, which is decorated by interiorpointing amide H atoms (Figures 2 and 3). Computationally, this sizable cavity is sufficiently spacious to accommodate up to two water molecules (Figure 2c). Experimentally, however, obtaining these water complexes is not straightforward. Examination of crystal structures unveils an absence of water molecules in 10, 11a, and 12, and the presence of up to two water molecules in 11b and 13 (Figure 4). In particular, 12 crystallized out with one methylene chloride molecul (CH2Cl2) sandwiched between two molecules of 12. These observations highlight strong dependence of water binding by pyridine foldamers on end group, oligomeric length, and even exterior side chain. Given that the water-containing crystals were grown from the crystallizing media where only trace amounts of water can be found, that is, CH2Cl2 for 11b, CH2Cl2/cyclohexane (1:1, v:v) for 13a and CHCl3/EtOH (1:1, v:v) for 13b, their binding affinities toward water molecules are high and selective. A difference in geometry apparently produces a significance difference in water binding. Specifically, 11b with a planar backbone binds just one water molecule, and 3D-shaped 13a and 13b each trap two water molecules in their helical cavity. Interestingly, molecules of 11b stack in a linear, cylindrical fashion with about 180° offset from each other. This forces two neighboring water molecules to stay in close contact with each other, giving rise to an unconventional water dimer that is solely mediated by hydrogen−hydrogen interaction (dH···H = 2.253 Å), rather than a typical H-bond. In all three water complexes, intermolecular H-bonds of varying strengths

Figure 4. Crystal structures of water complexes, encapsulating (a) an unconventional water dimer mediated by a H−H interaction as in 11b· H2O and (b,c) conventional water dimers as in 13·2H2O. (d) Intermolecular H-bonds between water dimer and backbone H-, Nand O-atoms, and intermolecular zigzag packing; small balls refer to atoms involved in forming H-bonds of within 3.0 Å with strong Hbonds further labeled with H-bond distances. The dimerization energies are listed below the structures.

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Accounts of Chemical Research provide primary forces to stabilize water molecules in 11b, 13a (Figure 4d), and 13b. The H-bonded aromatic backbones in 11b, 13a, and 13b provide respective stabilizing energies of 7.61, 10.73, and 7.97 kcal/mol for water molecules at the B3LYP/6-31G(d,p) level. Having respective binding energies of 2.22, 3.88, and 3.58 kcal/ mol, water dimers trapped in 11b, 13a, and 13b are destabilized by 1.63−2.99 kcal/mol when compared to the most stable hostfree water dimer (binding energy = 5.21 kcal/mol). The instability in trapped water dimers mostly results from the Hbonding-induced confined cavity, which does not match well with the geometry of the most stable constrain-free water dimer.

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HOLLOW NANOPORES FOR GUEST ENCAPSULATION27,36,37 To translate water-binding ability of aquafoldamers such as 11a and 13 into water-transporting function, one approach is to lengthen the helical backbone to about 34 Å in height for spanning hydrophobic membrane region. This, however, is exceptionally challenging since overall chemical yield for covalently linking about 40 pyridine rings via amide linkages would be so low that obtaining sufficient quantities of final material simply becomes impossible. A more atom-efficient approach is to assemble the aquafoldamer molecules noncovalently into membrane-active ensembles such as 1D channels. Nevertheless, the packing among these water complexes in the solid state is apparently disfavored toward the creation of well-organized 1D channels (Figure 4d). Such an observation is consistent with an interesting yet predominant occurrence of partial, that is, side-by-side, overlap of aromatic helical backbones of opposite handedness seen in many other helical foldamers, while the energetically more favored full overlap involving helices of the same handedness illustrated in Figure 5a has never been observed. This general phenomenon has puzzled us for some time. Careful structural analysis of many aromatic helical foldamers shows that most of them contain end groups (e.g., H atoms at the two ends of 13a), which electrostatically repel, rather than attract, one another. Our analysis also suggests exterior or interior bulky side chains present in most of known helices as another influential factor, preventing the backbone from forming an efficient full overlap. On these bases, a strategy was devised to focus on elimination of exterior and interior bulky side chains and further incorporation of two “sticky” groups of types I−III that contain electrostatically complementary functional groups at helical ends (Figure 5a). We thought that this new strategy might enable short helices to pile up to furnish onedimensionally aligned cavity-containing helical stacks via full overlaps from which hollow tubular cavities would be created for encapsulation of suitably sized guest molecules. A helically folded pentameric framework represented by pentamers 14 was chosen for testing against H-bond patterns I−III of varying structures and strengths (Figure 5a−c). Although the use of types II and III did not yield anticipated outcomes,48 type I did give rise to the formation of desired 1D helical stacks involving molecules of 14a with the same handedness via complementarities in both shape and end functionalities (Figure 5d). Concurrent with the formation of 1D chiral stacks, 1D hollow cavity of ∼2.8 Å in diameter is also created, which is decorated by both H-bond donors (amide protons) and acceptors (pyridine N atoms and ester O atoms) and found to contain 1D chains of methanol or dichloro-

Figure 5. (a) Conceptual design of one-dimensionally aligned helical stacks self-assembled via “sticky ends” of types I−III. Panels (b) and (c) depict pentameric structures for assessing the strategy outlined in (a). (d) Crystal structures of 14a·MeOH and 14a·CH2Cl2. The red and gray balls as well as those highlighted in dotted ovals in (d) refer to the complementary “sticky” end groups that seamlessly “glue” single-handed helical molecules of 14a, via numerous weak H-bonds of 2.44 Å in length, into a chiral column that encloses 1D chain of MeOH or CH2Cl2 molecules.

methane molecules. The type I H-bond found in crystal structure of 14a measures 2.44 Å in length and is determined to be 1.1 kcal/mol in strength at the level of B3LYP/6-31G(d,p) in gas phase. Noticeably, the energetic contribution by the “sticky” ends is not very substantial. This nevertheless implies that being attractive at the two helical ends, rather than repulsive as found in other synthetic helices, far outweighs the weakness of the attractive force. Under this scenario, the same handed helical molecules of 14b are also directed by type I “sticky” ends to pack on top of one another to form wellorganized 1D helical stacks.36 In this case, the protrusion of fluorine atoms toward cavity interior makes the cavity too small to be suitable for binding molecules as small as water and MeOH. For comparison, tetramer 12, unable to form a full helical turn, pentamers 13a and 13b, which possess a full helical turn E

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Figure 6. (a) Structure of 15. (b) H-bonded “sticky ends” in 15 found in the solid state. Panels (c)−(f) illustrate crystal structure of 15·2H2O, complementary end H atoms in gray and O atoms in red, and 1D water chain inside hollow cavity. Panels (g) and (h) show time-dependent changes in fluorescence intensity (λex = 460 nm, λem = 510 nm) of HPTS inside LUVs and in average diameter of LUVs (monitored at 400 nm) caused by 15 and other control compounds and blank solution.

but no “sticky” ends, and pentamers 14c and 14d, which contain either interior methoxy or exterior benzyl side chains, cannot form 1D helical stacks. In all cases, helices of opposite handedness interact with each other more strongly than those among the same handed helices. Surprisingly, a hexamer having just one more pyridine unit than pentamer 14a turns out to be incapable of producing organized 1D helical stacks, either.27 A computation-based comparative structural analysis between hexamer and 14a reveals a more significant protrusion from 1D columnar surface by the Cbz group in hexamer than that in 14a, likely accounting for why the Cbz group in hexamer has to be twisted to stay perpendicular to, instead of in parallel with, helical backbone. It is this twist that causes disruption of otherwise possibly formed 1D stacks. The above investigations show that the two “sticky” groups placed at the two helical ends do not always enable helical molecules to pack into well-defined 1D stacks. Pentameric backbone appears to be geometrically more optimized toward the formation of 1D structure than other analogous oligomers of up to hexamer. As a result of weak and fragile intermolecular H-bonds formed between “sticky” ends, the proper function to be performed by “sticky” ends seem to be greatly impeded by factors including a shortened helical backbone unable to provide sufficient driving forces as in 12, the existence of bulky interior or exterior groups as in 14c and 14b, and surface overprotrusion by such as Cbz group as in hexamer. More importantly, to promote efficient formation of 1D helical stacks and create 1D hollow cavities for hosting chains of small guest molecules, it is critical for the helical backbone to be

geometrically compatible with varying types of intermolecular forces. Such desirable compatibility not only facilitates a synergistic interplay between the attractive but weak end-toend interactions and the stronger aromatic π−π stacking forces to attain a full overlap of helical backbones, but also maximizes mutual stabilizations among the 1D columns via intercolumnar edge-to-edge contacts. Employing complementary “sticky” ends to direct chiral packing and create hollow cavities, these very first examples might inspire some further utilities in generating single-handed optically active helices in synthetic foldamers or polymers for interesting applications.

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AQUAPORES FOR WATER BINDING AND TRANSPORT27

Remarkably, regrowing or soaking crystals of 14a in watercontaining solvents and subsequent structural determination reveal that about 24−40% of MeOH molecules inside hollow cavity remain exchangeable by water molecules. This is contrary to the findings that analogous oligomers 11a and 13 readily accommodate up to two water molecules in their cavity,34,35 suggesting that water binding by these pyridine oligomers exhibit strong dependence on subtle difference in structure (e.g., end groups, oligomeric length or even exterior side chains). This further suggests that even though the hollow cavity in (14a)n displays higher binding affinities toward methanol or dichloromethane than water molecules, it is possible to generate, via structural modifications, the same type F

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Figure 7. (a) Top views of 1D water chains from crystal structures 15n·2H2O (n = 0−4). (b) Schematic illustration of the bifurcated H-bonding system composed of H-bonds H1 and H2 formed by two “sticky” ends in water-containing structures. (c) Crystal structure of 15·MeOH. (d) Comparative H-bond lengths for H1 and H2 in 15·MeOH.

(LUVs) of ∼250 nm diameter with pH inside the LUVs kept at 7.4 in PBS buffer. Proton transport was initiated by diluting the LUVs in the same PBS buffer at pH 5.5 to impose a proton gradient across the LUVs. Among oligomers 10−15, 14a and 15 result in the largest reductions in fluorescence intensity upon adding 1.45 mol % (relative to lipid) into the solution, and manifest themselves as the best proton transporters (Figure 6g). These proton transport functions expectedly should arise from their ability to pile up to create functional hollow cavities in the membrane in the same way as the pore formation seen in the solid state. Using the same type of LUVs and experimental setup, water transport was monitored by dynamic light scattering (DLS) experiments for 400 min, revealing time-dependent variations in average diameter of LUVs upon additions of oligomers 10− 15. While an average particle size of ∼350 nm or above for LUVs is well maintained within a period of 7 h for solution containing 15, marginal changes of 5304 against CH2Cl2, respectively. A selectivity factor of 5304 was simply derived from the fact that crystals of 15·2H2O were grown from 15containing anhydrous CH2Cl2, which contains ≤0.001% water by weight. Determining selectivity factor against MeOH is more complicated, and involves regrowing crystals of 15·2H2O from 15-containing CH2Cl2 (1 mL) via slow diffusion of H2O (20 μL) containing MeOH at varying volumes (20, 100, 200, and 800 μL for 151·2H2O, 152·2H2O, 153·2H2O, and 154· 2H2O, respectively) at room temperature for 10−15 days. Under the specified conditions, invariable trapping of only water molecules inside aquapores was observed. Topographically, water chains in 15·2H2O, 152·2H2O, and 154·2H2O are more akin to one another but significant differences do exist between them and those in 151·2H2O and 153·2H2O (Figure 7a). Other structural differences include sizable variation in helical pitch, aromatic π−π stacking distance, H-bond length in water chain (Figure 6f) and in both H1 and H2 (Figure 7b). Many more structural changes in helical backbone also can be observed. These structural variations result in considerable energetic variation in increasing order of sticky” ends < host− guest interactions < H-bonds in water chains < aromatic π−π stacking interaction. Further, total binding energy calculation reveals that the use of 39-fold excess of methanol during crystal growth causes a dramatic impact on the aquapore structure, abruptly decreasing its energy and stability from a range of 59.29−62.55 kcal/mol for 15n·2H2O (n = 0−3) to 54.66 kcal/ mol for 154·2H2O. Even more interesting dramatic dynamics is observed around “sticky” ends by comparing structure of 15·MeOH with any water-containing structure such as 151·2H2O (Figure 7b vs d). In 15·MeOH, H-bond H1 is shorter than H2 (Figure 7d), but this relative magnitude is reversed in 151·2H2O (Figure 7b). These findings demonstrate the structural robustness of hollow aquapores in aligning water molecules and in holding 1D water chains. In response to external stimuli such as varying amounts of methanol, the water-containing structures do undergo dynamic rearrangements, and differ subtly in many structural aspects and quite significantly in energy. Energetically, the use of excessive amounts of methanol during crystal growth exerts the largest impact on aromatic π−π stacking and very substantial influences on host−guest interactions and structures of both water chain and “sticky” ends.

biomimetic membranes to produce porous nanofiltration membrane permeable to only water molecules to “droughtproof” mankind on an increasingly thirsty planet via seawater desalination and wastewater reclamation. Although no clear strategies on this front have been demonstrated, it is our sincere hope and firm belief that lessons and insights learned from recently emerged efforts toward creation of synthetic water channels23−27 will serve to further catalyze the field of research in both fundamental and practical settings, and help to translate basic science into practical benefits in the near future.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Yanping Huo earned his B.S. in chemistry from Hebei University and Ph.D. from Chinese Academy of Sciences. He did his postdoctoral work at the Shanghai Institute of Organic Chemistry, worked as a research assistant at the University Hong Kong, and is currently Professor at the Guangdong University of Technology. Huaqiang Zeng earned his B.S. in chemistry from the University of Science and Technology of China and Ph.D. from the State University of New York at Buffalo. After his postdoctoral work at the Scripps Research Institute, he joined the National University of Singapore as Assistant Professor in 2006, and moved to the Institute of Bioengineering and Nanotechnology as Team Leader in 2014.

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ACKNOWLEDGMENTS This work was supported by the Institute of Bioengineering and Nanotechnology (Biomedical Research Council, Agency for Science, Technology and Research, Singapore) and the Environment & Water Industry Programme Office (EWI, 1501-IRIS-03).

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REFERENCES

(1) Matile, S.; Som, A.; Sordé, N. Recent synthetic ion channels and pores. Tetrahedron 2004, 60, 6405−6435. (2) Gokel, G. W.; Carasel, I. A. Biologically active, synthetic ion transporters. Chem. Soc. Rev. 2007, 36, 378−389. (3) Matile, S.; Vargas Jentzsch, A.; Montenegro, J.; Fin, A. Recent synthetic transport systems. Chem. Soc. Rev. 2011, 40, 2453−2474. (4) Vargas Jentzsch, A.; Hennig, A.; Mareda, J.; Matile, S. Synthetic Ion Transporters that Work with Anion−π Interactions, Halogen Bonds, and Anion−Macrodipole Interactions. Acc. Chem. Res. 2013, 46, 2791−2800. (5) Sakai, N.; Matile, S. Synthetic Ion Channels. Langmuir 2013, 29, 9031−9040. (6) Montenegro, J.; Ghadiri, M. R.; Granja, J. R. Ion Channel Models Based on Self-Assembling Cyclic Peptide Nanotubes. Acc. Chem. Res. 2013, 46, 2955−2965. (7) Fyles, T. M. How Do Amphiphiles Form Ion-Conducting Channels in Membranes? Lessons from Linear Oligoesters. Acc. Chem. Res. 2013, 46, 2847−2855. (8) Otis, F.; Auger, M.; Voyer, N. Exploiting Peptide Nanostructures To Construct Functional Artificial Ion Channels. Acc. Chem. Res. 2013, 46, 2934−2943. (9) Gokel, G. W.; Negin, S. Synthetic Ion Channels: From Pores to Biological Applications. Acc. Chem. Res. 2013, 46, 2824−2833. (10) Davis, A. P.; Sheppard, D. N.; Smith, B. D. Development of synthetic membrane transporters for anions. Chem. Soc. Rev. 2007, 36, 348−357.

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CONCLUSIONS Taking advantage of an experimental-theoretical synergy and “sticky” ends, our de novo design approach results in the discovery of pyridine-based synthetic water channels as a new addition into the growing list of water-transporting channel systems for which limited examples with dramatically different structures and designs have been demonstrated only very recently. Recognizing that the field is still in its infancy, it would be wise, nevertheless, to start pondering the next grand step. This involves the integration of established water channels into H

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Accounts of Chemical Research

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DOI: 10.1021/acs.accounts.6b00051 Acc. Chem. Res. XXXX, XXX, XXX−XXX