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An Artificial Molecular Shuttle Operates in Lipid Bilayers for Ion Transport
Abstract
Inspired by natural biomolecular machines, synthetic molecular-level machines have been proven to perform well-defined mechanical tasks and measurable work. To mimic the function of channel proteins, we herein report the development of a synthetic molecular shuttle, [2]rotaxane 3, as a unimolecular vehicle that can be inserted into lipid bilayers to perform passive ion transport through its stochastic shuttling motion. The [2]rotaxane molecular shuttle is composed of an amphiphilic molecular thread with three binding stations, which is interlocked in a macrocycle wheel component that tethers a K⁺ carrier. The structural characteristics enable the rotaxane to transport ions across the lipid bilayers, similar to a cable car, transporting K⁺ with an EC50 value of 1.0 μM (3.0 mol% relative to lipid). We expect that this simple molecular machine will provide new opportunities for developing more effective and selective ion transporters.
... For RT molecules, we selected six different voltages of 50 mV, 100 mV, 150 mV, -50 mV, -100 mV, and -150 mV for testing. For RR [2], 50 mV, 100 mV, 120 mV, -50 mV, -100 mV, -120 mV were selected. (The selected voltage has no special purpose and at least three signals per group of voltages were collected). ...
... Plots of kobs against concentrations of a-b) RT (0.25-5.0 μM) and c-d) RR[2] (0.25-5.0 μM). a) and c) are the representative one group of data for kobs fitting by a first-order exponential decay equation, b) and d) are the fitting treatments for linear relationship between kobs and concentrations.4.5 Ion selectivity studies across LUVs⊃HPTSFig. ...
... Clion influx across LUVs⊃lucigenin assay (Na2SO4 was used to replace intra-and extra-vesicular NaNO3) upon addition of a) RT (0-9.0 μM) and b) RR[2] (0-9.0 μM).6. Planar Bilayer Conductance Measurements6.1 General experiments for RT and RR[2]General process: A CDCl3 solution of 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) was evaporated using a stream of nitrogen. ...
Inspired by the design criterion of heteroditopic receptor for ion-pair binding, we herein describe a new strategy to construct a rotaxane transporter ( RR[2] ) for K ⁺ /Cl – cotransport. The use of rigid...
... Fortunately, thanks to the development of artificial ion channel technology, the above problems may be effectively solved. Artificial ion channels are mimics of natural channel proteins that can also transmit certain ions highly selectively [26][27][28][29]. Artificial potassium channels have shown promising tumor suppression effects [30][31][32][33][34]. ...
... [5] Indeed, we and others have demonstrated that MIMs not only raise the bar in terms of anion affinity, but crucially provide a strategy to augment selectivity profiles through a 'mechanical bond effect'. [6][7][8][9][10][11][12][13][14][15] Surprisingly, however, the use of interlocked structures to mediate ion transport remains rare and have thus far been restricted to [2]rotaxane architectures [16][17][18][19] and a molecular knot based ion channel system. [20] Lewis acidic sigma-hole interactions such as halogen bonding (XB) and chalcogen bonding (ChB) are remarkably potent non-covalent means by which anion recognition can be achieved, exhibiting dramatically enhanced affinities relative to traditional strategies including hydrogen bonding (HB), even in highly competitive aqueous media. ...
The first examples of [2]catenanes capable of selective anion transport across a lipid bilayer are reported. The neutral halogen bonding (XB) [2]catenanes were prepared via a chloride template‐directed strategy in an unprecedented demonstration of using XB⋅⋅⋅anion interactions to direct catenane assembly from all‐neutral components. Anion binding experiments in aqueous‐organic solvent media revealed strong halide over oxoanion selectivity, and a marked enhancement in the chloride and bromide affinities of the catenanes relative to their constituent macrocycles. The catenanes additionally displayed an anti‐Hofmeister binding preference for bromide over the larger iodide anion, illustrating the efficacy of employing sigma‐hole interactions in conjunction with the mechanical bond effect to tune receptor selectivity. Transmembrane anion transport studies conducted in POPC LUVs revealed that the catenanes were more effective anion transporters than the constituent macrocycles, with high chloride over hydroxide selectivity, which is critical to potential therapeutic applications of anionophores. Remarkably these outperform existing acyclic halogen bonding anionophores with regards to this selectivity. Record chloride over nitrate anion transport selectivity was also observed. This represents a rare example of the direct translation of intrinsic anion binding affinities to anion transport behaviour, and demonstrates the key role of the catenane mechanical bond effect for enhanced anion transport selectivity.
... In an effort to imitate both the structure and function of natural ion transport systems, the attention of the scientific community continuously shifted from unifunctional ion channels [12] to the development of small molecule-based cation channels. [13][14][15][16][17][18][19][20][21] Not only are cation channels the focus of current molecular recognition research, but synthetic anion channels [22][23][24][25][26][27][28][29][30][31] are also being developed with the intention of emulating natural anion channels and their activities. However, synthetic cation-anion symporter channels have received limited attention in the scientific community due to difficulties in decorating the channel selectivity filter to transport both cation and anion selectively. ...
The structural tropology and functions of natural cation‐anion symporting channels have been continuously investigated due to their crucial role in regulating various physiological functions. To understand the physiological functions of the natural symporter channels, it is vital to develop small‐molecule‐based biomimicking systems that can provide mechanistic insights into the ion‐binding sites and the ion‐translocation pathways. Herein, we report a series of bis((R)‐(−)‐mandelic acid)‐linked 3,5‐diaminobenzoic acid based self‐assembled ion channels with distinctive ion transport ability. Ion transport experiment across the lipid bilayer membrane revealed that compound 1 b exhibits the highest transport activity among the series, and it has interesting selective co‐transporting functions, i.e., facilitates K⁺/ClO4⁻ symport. Electrophysiology experiments confirmed the formation of supramolecular ion channels with an average diameter of 6.2±1 Å and single channel conductance of 57.3±1.9 pS. Selectivity studies of channel 1 b in a bilayer lipid membrane demonstrated a permeability ratio of PCl-/PK+=0.053±0.02 ${{P}_{{Cl}^{-}}/{P}_{{K}^{+}}=0.053\pm 0.02}$ , PClO4-/PCl-=2.1±0.5 ${{P}_{{ClO}_{4}^{-}}/{P}_{{Cl}^{-}}=2.1\pm 0.5}$ , and PK+/PNa+=1.5±1, ${{P}_{{K}^{+}}/{P}_{{Na}^{+}}=1.5\pm 1,}$ indicating the higher selectivity of the channel towards KClO4 over KCl salt. A hexameric assembly of a trimeric rosette of 1 b was subjected to molecular dynamics simulations with different salts to understand the supramolecular channel formation and ion selectivity pattern.
... [44] Qu and co-workers have utilized the molecular motion of a macrocycle along a rotaxane's axle to transport K + across lipid bilayer membranes. [45] They subsequently incorporated an azobenzene unit into the axle 27 to photo-modulate its shuttling behavior, and hence cation transport capability ( Figure 19). [46] The E isomer was found to be around 5 times more active compared to the Z isomer, which was rationalized by the faster shuttling of the crown ether macrocycle along the axle, which is inhibited in the non-planar Z state. ...
Synthetic supramolecular ion transporters find applications as potential therapeutics and as tools for engineering functional membranes. Stimuli‐responsive systems enable external control over transport, which is necessary for targeted activation. The Minireview provides an overview of current approaches to developing stimuli‐responsive ion transport systems, including channels and mobile carriers, that can be controlled using photo or redox inputs.
... The introduction of artificial molecular machines in bilayer membranes is an interesting way to affect their behavior in terms of permeability toward different substrates. 85,86 A further development in this direction would be attained by exploiting the directionality of molecular motors, which could on the long-term enable the active transport of molecular substrates across the membrane against a concentration gradient. Preliminary steps in this field span from less complicated systems up to highly articulated and tailored architectures. ...
Accurate control of long-range motion at the molecular scale holds great potential for the development of ground-breaking applications in energy storage and bionanotechnology. The past decade has seen tremendous development in this area, with a focus on the directional operation away from thermal equilibrium, giving rise to tailored man-made molecular motors. As light is a highly tunable, controllable, clean, and renewable source of energy, photochemical processes are appealing to activate molecular motors. Nonetheless, the successful operation of molecular motors fueled by light is a highly challenging task, which requires a judicious coupling of thermal and photoinduced reactions. In this paper, we focus on the key aspects of light-driven artificial molecular motors with the aid of recent examples. A critical assessment of the criteria for the design, operation, and technological potential of such systems is provided, along with a perspective view on future advances in this exciting research area.
... [20,21] Similar thermodynamic principles have been also recently exploited by synthetic chemists for the development of a series of innovative artificial molecular motors capable of using various sources of energy, and of producing specific tasks. [22][23][24][25][26][27][28][29][30][31][32] Among them, light-driven rotary motors [18,[33][34][35][36] introduced by the pioneering work of Ben Feringa and his co-workers [37] are of particular interest because (i) their structure is made of a very small number of atoms; (ii) they use light as a source of energy, which can be controlled both temporally and spatially, and which does not generate waste; (iii) they can reach high functioning frequencies under appropriate conditions; [38,39] and (iv) they can deliver high work and force. [40][41][42] In the present study, we focus on second generation light-driven rotary motors, [43] in which alternating photoisomerization and thermal helix inversion steps lead to the continuous and unidirectional rotation of their rotor part around the double bond and relative to their stator part (Figure 1, with rotor in blue and stator in red). ...
The unidirectional rotation of chemically crosslinked light‐driven molecular motors is shown to progressively shift the swelling equilibrium of hydrogels. The concentration of molecular motors and the initial strand density of the polymer network are key parameters to modulate the macroscopic contraction of the material, and both parameters can be tuned using polymer chains of different molecular weights. These findings led to the design of optimized hydrogels revealing a half‐time contraction of approximately 5 min. Furthermore, under inhomogeneous stimulation, the local contraction event was exploited to design useful bending actuators with an energy output 400 times higher than for previously reported self‐assembled systems involving rotary motors. In the present configuration, we measure that a single molecular motor can lift up loads of 200 times its own molecular weight.
... Nanoparticles based delivery is much more efficient as compared to the physical methods due to low immunogenicity and target selectivity. This type of delivery is mediated by a variety of nanoparticles, such as lipids, cholesterol, and other nanoparticles [92,93]. Lipids nanoparticle-based delivery effectively delivers the CRISPR/Cas system into the target in vivo system employed for genome editing [94,95]. ...
Chimeric Antigen Receptor (CAR) T therapy has shown remarkable success in discovering novel CAR-T cell products for treating B-cell malignancies. Despite of successful results from clinical trials, CAR-T cell therapy is ineffective for long-term disease progression. Numerous challenges of CAR-T cell immunotherapy such as cell dysfunction, cytokine-related toxicities, TGF-β resistance, GVHD risks, antigen escape, restricted trafficking, and tumor cell infiltration still exist that hamper the safety and efficacy of CAR-T cells for malignancies. The accumulated data revealed that these challenges could be overcome with the advanced CRISPR genome editing technology, which is the most promising tool to knockout TRAC and HLA genes, inhibiting the effects of dominant negative receptors (PD-1, TGF-β, and B2M), lowering the risks of cytokine release syndrome (CRS), and regulating CAR-T cell function in the tumor microenvironment (TME). CRISPR technology employs DSB-free genome editing methods that robustly allow efficient and controllable genetic modification. The present review explored the innovative aspects of CRISPR/Cas9 technology for developing next-generation/universal allogeneic CAR-T cells. We addressed the ongoing status of clinical trials of CRISPR/Cas9-engineered CAR-T cells against cancer and pointed out the off-target effects associated with CRISPR/Cas9 genome editing. It is concluded that CAR-T cells modified by CRISPR/Cas9 significantly improved antitumor efficacy in a cost-effective manner that provides opportunities for novel cancer immunotherapies.
DNA binding transcription factors possess the ability to interact with lipid membranes to construct ion-permeable pathways. Herein, we present a thiazole-based DNA binding peptide mimic TBP2, which forms transmembrane ion channels, impacting cellular ion concentration and consequently stabilizing G-quadruplex DNA structures. TBP2 self-assembles into nanostructures, e.g., vesicles and nanofibers and facilitates the transportation of Na⁺ and K⁺ across lipid membranes with high conductance (~0.6 nS). Moreover, TBP2 exhibits increased fluorescence when incorporated into the membrane or in cellular nuclei. Monomeric TBP2 can enter the lipid membrane and localize to the nuclei of cancer cells. The coordinated process of time-dependent membrane or nuclear localization of TBP2, combined with elevated intracellular cation levels and direct G-quadruplex (G4) interaction, synergistically promotes formation and stability of G4 structures, triggering cancer cell death. This study introduces a platform to mimic and control intricate biological functions, leading to the discovery of innovative therapeutic approaches.
Molecular machines are key to cellular activity where they are involved in converting chemical and light energy into efficient mechanical work. During the last 60 years, designing molecular structures capable of generating unidirectional mechanical motion at the nanoscale has been the topic of intense research. Effective progress has been made, attributed to advances in various fields such as supramolecular chemistry, biology and nanotechnology, and informatics. However, individual molecular machines are only capable of producing nanometer work and generally have only a single functionality. In order to address these problems, collective behaviors realized by integrating several or more of these individual mechanical units in space and time have become a new paradigm. In this review, we comprehensively discuss recent developments in the collective behaviors of molecular machines. In particular, collective behavior is divided into two paradigms. One is the appropriate integration of molecular machines to efficiently amplify molecular motions and deformations to construct novel functional materials. The other is the construction of swarming modes at the supramolecular level to perform nanoscale or microscale operations. We discuss design strategies for both modes and focus on the modulation of features and properties. Subsequently, in order to address existing challenges, the idea of transferring experience gained in the field of micro/nano robotics is presented, offering prospects for future developments in the collective behavior of molecular machines.
Developing synthetic molecular devices for controlling ion transmembrane transport is a promising research field in supramolecular chemistry. These artificial ion channels provide models to study ion channel diseases and have huge potential for therapeutic applications. Compared with self‐assembled ion channels constructed by intermolecular weak interactions between smaller molecules or cyclic compounds, metallacage‐based ion channels have well‐defined structures and can exist as single components in the phospholipid bilayer. A naphthalene diimide‐based artificial chloride ion channel is constructed through efficient subcomponent self‐assembly and its selective ion transport activity in large unilamellar vesicles and the planar lipid bilayer membrane by fluorescence and ion‐current measurements is investigated. Molecular dynamics simulations and density functional theory calculations show that the metallacage spans the entire phospholipid bilayer as an unimolecular ion transport channel. This channel transports chloride ions across the cell membrane, which disturbs the ion balance of cancer cells and inhibits the growth of cancer cells at low concentrations.
Natural organisms have developed various biological ion channels/transporters to maintain normal life activities to adapt to changing environments. Significantly, ion transporters with active ion transport property show much more controllability on these activities due to a variety of external stimuli, giving guidance to construct artificial counterparts for overcoming the issues in simple nanofluidic systems restricted by self‐diffusive ion transport. Herein, a 2D nanofluidic system based on a Janus membrane (i.e., JM) is constructed, which can achieve light‐driven active ion transport and do favor for ionic power harvesting in electrolyte systems with equal concentrations. The JM is obtained through sequentially assembled montmorillonite (MMT) decorated with photoelectric molecules (i.e., PMMT) and MXene nanosheets. Due to the formed intramembrane electric field and temperature gradient caused by the efficient charge separation and localized thermal excitation under light illumination, a photovoltaic‐driven force and thermo‐osmotic are generated for preferential ion transport. In addition, the unidirectional active transport is employed to harvest ionic power, showing an output power density of 2.0 mW m⁻² and a high‐performance energy conversion efficiency of 8.3 × 10⁻⁴%. The effects of the light intensity, electrolyte concentration and species on energy conversion performance are investigated, showing the university for ionic power harvesting.
Aiming at the construction of novel stimuli‐responsive fluorescent system with precisely tunable emissions, the typical 9,14‐diphenyl‐9,14‐dihydrodibenzo[a, c]phenazine (DPAC) luminogen with attractive vibration‐induced emission (VIE) behavior has been introduced into [2]rotaxane as a stopper. Taking advantage of their unique dual stimuli‐responsiveness towards solvent and anion, the resultant [2]rotaxanes reveal both tunable VIE and switchable circularly polarized luminescence (CPL). Attributed to the formation of mechanical bonds, DPAC‐functionalized [2]rotaxanes display interesting VIE behaviors including white‐light emission upon the addition of viscous solvent, as evaluated in detail by femtosecond transient absorption (TA) spectra. In addition, ascribed to the regulation of chirality information transmission through anion‐induced motions of chiral wheel, the resolved chiral [2]rotaxanes reveal unique switchable CPL upon the addition of anion, leading to significant increase in the dissymmetry factors (glum) values with excellent reversibility. Interestingly, upon doping the chiral [2]rotaxanes in stretchable polymer, the blend films reveal remarkable emission change from white light to light blue with significant 6.5‐fold increase in glum values up to ‐0.035 under external tensile stresses. This work provides not only a new design strategy for developing molecular systems with fluorescent tunability but also a novel platform for the construction of smart chiral luminescent materials for practical use.
Aiming at the construction of novel stimuli‐responsive fluorescent system with precisely tunable emissions, the typical 9,14‐diphenyl‐9,14‐dihydrodibenzo[a, c]phenazine (DPAC) luminogen with attractive vibration‐induced emission (VIE) behavior has been introduced into [2]rotaxane as a stopper. Taking advantage of their unique dual stimuli‐responsiveness towards solvent and anion, the resultant [2]rotaxanes reveal both tunable VIE and switchable circularly polarized luminescence (CPL). Attributed to the formation of mechanical bonds, DPAC‐functionalized [2]rotaxanes display interesting VIE behaviors including white‐light emission upon the addition of viscous solvent, as evaluated in detail by femtosecond transient absorption (TA) spectra. In addition, ascribed to the regulation of chirality information transmission through anion‐induced motions of chiral wheel, the resolved chiral [2]rotaxanes reveal unique switchable CPL upon the addition of anion, leading to significant increase in the dissymmetry factors (glum) values with excellent reversibility. Interestingly, upon doping the chiral [2]rotaxanes in stretchable polymer, the blend films reveal remarkable emission change from white light to light blue with significant 6.5‐fold increase in glum values up to −0.035 under external tensile stresses. This work provides not only a new design strategy for developing molecular systems with fluorescent tunability but also a novel platform for the construction of smart chiral luminescent materials for practical use.
A biphenyl-23-crown-7 ether (BP23C7) is synthesized in 86% yield from commercially available starting materials. BP23C7 forms pseudo[2]rotaxane with a dibenzylammonium ion (DBA+), exhibiting a good association constant value (ka =...
Impossible' rotaxanes, which are constituted by interlocked components without obvious binding motifs, have attracted the interest of the mechanically interlocked molecules (MIMs) community. Within the synthetic efforts reported in the last decades towards the preparation of MIMs, some innovative protocols for accessing 'impossible' rotaxanes have been developed. This short review highlights different selected synthetic examples of 'impossible' rotaxanes, as well as suggests some future directions of this research area.
Potassium channels represent the most prevalent class of ion channels, exerting regulatory control over numerous vital biological processes, including muscle contraction, neurotransmitter release, cell proliferation, and apoptosis. The seamless integration of astonishing functions into a sophisticated structure, as seen in these protein channels, inspires the chemical community to develop artificial versions, gearing toward simplifying their structure while replicating their key functions. In particular, over the past ten years or so, a number of elegant artificial potassium transporters have emerged, demonstrating high selectivity, high transport efficiency or unprecedented transport mechanisms. In this review, we will provide a detailed exposition of these artificial potassium transporters that are derived from a single molecular backbone or self-assembled from multiple components, with their respective structural designs, channel functions, transport mechanisms and biomedical applications thoroughly reviewed.
Nature embeds some of its molecular machinery, including ion pumps, within lipid bilayer membranes. This has inspired chemists to attempt to develop synthetic analogues to exploit membrane confinement and transmembrane potential gradients, much like their biological cousins. In this perspective, we outline the various strategies by which molecular machines—molecular systems in which a nanomechanical motion is exploited for function—have been designed to be incorporated within lipid membranes and utilized to mediate transmembrane ion transport. We survey molecular machines spanning both switches and motors, those that act as mobile carriers or that are anchored within the membrane, mechanically interlocked molecules, and examples that are activated in response to external stimuli.
Research into mechanically interlocked luminescent molecules (MILMs), which is the overlapping of mechanically interlocked molecules and luminescent molecules, has intensified over the past few decades. These studies have tapped into and exploited the benefits of mechanically interlocked structures to achieve outstanding and stimulus‐responsive optical characteristics, resulting in the synthesis of new types of luminescent systems and exploring their potential uses in different applications. This review describes the salient attributes of MILMs and showcases some of the latest advancements in this field of research.
Natural molecular machines have inspired the development of artificial molecular machines, which have the potential to revolutionize several areas of technology. Artificial molecular machines commonly employ molecular switches, molecular motors, and molecular shuttles as fundamental building blocks. The observation of artificial molecular machines constructed by these building blocks can be highly challenging due to their small sizes and intricate behaviors. The use of modern instrumentation and advanced observational techniques plays a crucial role in the observation and characterization of molecular machines. Furthermore, a well‐designed molecular structure is also a critical factor in making molecular machines more observable. This review summarizes the common methods from diverse perspectives used to observe molecular machines and emphasizes the significance of comprehending their behaviors in the design of superior artificial molecular machines.
The development of stimuli‐responsive artificial H+/Cl‐ ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non‐covalently stapled self‐assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co‐transport of H+/Cl‐ across the membrane with H+/Cl‐ transport selectivity of 6.0. Upon photoirradiation of the caged C4F‐L for 10 min, 90% of ion transport efficiency can be restored, giving rise to a 10.5‐fold enhancement in cytotoxicity against human colorectal cancer cells (IC50 = 8.5 μM). The mechanism underlying cancer cell death mediated by the H+/Cl‐ channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F‐L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 μM.
The development of stimuli‐responsive artificial H⁺/Cl⁻ ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non‐covalently stapled self‐assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co‐transport of H⁺/Cl⁻ across the membrane with H⁺/Cl⁻ transport selectivity of 6.0. Upon photoirradiation of the caged C4F‐L for 10 min, 90 % of ion transport efficiency can be restored, giving rise to a 10.5‐fold enhancement in cytotoxicity against human colorectal cancer cells (IC50=8.5 μM). The mechanism underlying cancer cell death mediated by the H⁺/Cl⁻ channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F‐L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 μM.
Molecular engineering seeks to create functional entities for modular use in the bottom-up design of nanoassemblies that can perform complex tasks. Such systems require fuel-consuming nanomotors that can actively drive downstream passive followers. Most artificial molecular motors are driven by Brownian motion, in which, with few exceptions, the generated forces are non-directed and insufficient for efficient transfer to passive second-level components. Consequently, efficient chemical-fuel-driven nanoscale driver–follower systems have not yet been realized. Here we present a DNA nanomachine (70 nm × 70 nm × 12 nm) driven by the chemical energy of DNA-templated RNA-transcription-consuming nucleoside triphosphates as fuel to generate a rhythmic pulsating motion of two rigid DNA-origami arms. Furthermore, we demonstrate actuation control and the simple coupling of the active nanomachine with a passive follower, to which it then transmits its motion, forming a true driver–follower pair.
The first examples of [2]catenanes capable of selective anion transport across a lipid bilayer are reported. The neutral halogen bonding (XB) [2]catenanes were prepared via a chloride template‐directed strategy in an unprecedented demonstration of using XB∙∙∙anion interactions to direct catenane assembly from all‐neutral components. Anion binding experiments in aqueous‐organic solvent media revealed strong halide over oxoanion selectivity, and a marked enhancement in the chloride and bromide affinities of the catenanes relative to their constituent macrocycles. The catenanes displayed an anti‐Hofmeister binding preference for bromide over the larger iodide anion, illustrating the efficacy of employing sigma‐hole interactions in conjunction with the mechanical bond effect to tune receptor selectivity. Transmembrane anion transport studies conducted in POPC LUVs revealed that the catenanes were more effective anion transporters than the constituent macrocycles, with high chloride over hydroxide selectivity, which is critical to potential therapeutic applications of anionophores. Remarkably these outperform existing acyclic halogen bonding anionophores with regards to this selectivity. Record chloride over nitrate anion transport selectivity was also observed. This represents a rare example of the direct translation of intrinsic anion binding affinities to anion transport behaviour, and demonstrates the key role of the catenane mechanical bond effect for enhanced anion transport selectivity.
While controlling the wheel shuttling of protype [2]rotaxanes have been readily achieved which promotes the development of intelligent supramolecular systems and materials, it remains a grand challenge to access higher...
The structural tropology and functions of natural cation‐anion symporting channels have been continuously investigated due to their crucial role in regulating various physiological functions. To understand the physiological functions of the natural symporter channels, it is vital to develop small molecule‐based biomimicking systems that can provide mechanistic insights into the ion‐binding sites and the ion‐translocation pathways. Herein, we report a series of bis((R)‐(‒)‐mandelic acid)‐linked 3,5‐diaminobenzoic acid‐based self‐assembled ion channels with distinctive ion transport ability. Ion transport experiment across the lipid bilayer membrane revealed that compound 1b exhibits the highest transport activity among the series, and it has interesting selective co‐transporting functions, i.e., facilitates K+/ClO4‒ symport. Electrophysiology experiments confirmed the formation of supramolecular ion channels with an average diameter of 6.2 ± 1 Å and single channel conductance of 57.3 ± 1.9 pS. Selectivity studies of channel 1b in BLM demonstrated the permeability ratio of PCl‒/PK+ = 0.053 ±0.02, PClO4‒/PCl‒ = 2.1 ± 0.5, and PK+/PNa+ = 1.5 ± 1, respectively, indicating the higher selectivity of the channel towards KClO4 over KCl salt. A hexameric assembly of a trimeric rosette of 1b was subjected to molecular dynamics simulations with different salts to understand the supramolecular channel formation and ion selectivity pattern.
Synthetic molecules that can mediate the coupled transport of Cl− with K+ and/or Na+ across the lipid bilayers have aroused great interest due to their potential as a novel therapeutic strategy by disrupting cellular ion homeostasis. Based on the structural advantages of molecular rotaxanes, we herein show that two rotaxane-based transporters [2]R and [3]R induce coupled K+/Cl− channel transport by introducing Cl− recognition sites in the thread and K+ binding group in the wheel, respectively. The well-designed molecular structures allow the insertion of unimolecular rotaxanes into the lipid bilayer, thus achieving effective ion transport by means of thermodynamically controlled movement and driven by the difference in ion concentration inside and outside the vesicles. In addition, the use of a three-component rotaxane can accelerate ion transport through a cooperative shuttle-relay mechanism in which two wheels move along the thread in the lipid membrane, thereby enabling [3]R to have higher ion transport capacity. This work represents a major advance in the use of rotaxane molecules to accomplish more complex and effective tasks.
Synthetic supramolecular ion transporters find applications as potential therapeutics and as tools for engineering functional membranes. Stimuli‐responsive systems enable external control over transport, which is necessary for targeted activation. The Minireview provides an overview of current approaches to developing stimuli‐responsive ion transport systems, including channels and mobile carriers, that can be controlled using photo or redox inputs.
The pH regulation of transmembrane ion transport is critical for biological processes and has a direct implication on diseases such as cancer. Synthetic transporters that can be regulated using pH show promise as therapeutic agents. This review highlights the importance of the fundamental principles of acid-base chemistry in achieving pH regulation. A systematic classification of transporters based on the pKa of their pH-responsive units aids in correlating the pH regulation of ion transport with the molecular structure. This review also summarises the applications of these transporters and their efficacy in cancer therapy.
Aiming at the construction of novel soft actuators through the amplified motions of molecular machines at the nanoscale, the design and synthesis of a new family of photoresponsive rotaxane-branched dendrimers through an efficient controllable divergent approach was successfully realized for the first time. In the third-generation rotaxane-branched dendrimers, up to 21 azobenzene-based rotaxane units located at each branch, thus making them the first successful synthesis of light-control integrated artificial molecular machines. Notably, upon alternative irradiation with UV and visible light, photoisomerization of the azobenzene stoppers leads to the collective and amplified motions of the precisely arranged rotaxane units, resulting in controllable and reversible dimension modulation of the integrating photoresponsive rotaxane-branched dendrimers in solution. Moreover, novel macroscopic soft actuators were further constructed based on these photoresponsive rotaxane-branched dendrimers, which revealed fast shape transformation behaviors with an actuating speed up to 21.2 ± 0.2° s-1 upon ultraviolet irradiation. More importantly, the resultant soft actuators could produce mechanical work upon light control that has been further successfully employed for weight-lifting and cargo transporting, thus laying the foundation toward the construction of novel smart materials that can perform programmed events.
Hinge motion is observed in macrocyclic, mortise‐type molecular hinges using variable temperature NMR spectroscopy. The data is consistent with dynamic hinging from a folded‐to‐extended‐to‐folded enantiomeric state. Crystallographic and solution structures of the folded states are reported. Chemical shift predictions derived from crystallographic data corroborate fully revolute hinge motion. The rate of hinging is affected by steric congestion at the hinge axis. A macrocycle containing glycine, 1, hinges faster than one comprising aminoisobutyric acid, 2. The free energies of activation, ΔG≠, for 1 and 2 were determined to be 13.3±0.3 kcal/mol and 16.3±0.3 kcal/mol, respectively. This barrier is largely independent of solvent across those surveyed (CD3OD, CD3CN, DMSO‐d6, pyridine‐d5, D2O). Experiment and computation predict energy barriers that are consistent with disruption of an intramolecular network of hydrogen bonds. DFT calculations reveal a pathway for hinge motion.
Artificial functional ionophores are essential for selective transmembrane ion transport since ion transport through biological membranes is an essential phenomenon and its disruption causes a variety of illnesses. Herein, we...
Objective: to form doctrinal bases and mechanics of legal regulation of using medical nanorobots; to conceptualize the idea of nanorobotics law within the frameworks of its basic definitions, safety norms, risks, typology of devices, and legal parameters of technological terminology.Methods: the cognition tools are represented in the form of integration between general scientific and modern special legal methods (including the methods of comparative legal studies, legal modeling and juridical forecasting, NBICS-convergence), which, taken as a whole, allow distinguishing in the study object not only juridical proper, but also anthropological, biomedical, informational, and mechanistic research projections.Results: the author’s definition of the medical nanorobot concept was formulated; the legal content and quasi-legal aspects of the definition that are important for the theoretical and applied development of terminology were investigated; the signs of related concepts (biomedical robot, nanorobotic system, medical nanorobotic system) were identified and logical connections between them were established; the classification of the main types of risks associated with the practical use of medical nanorobots was carried out; the list of theoretical and legal contradictions that are potentially capable of negatively affecting the future development of regulatory practice was revealed; the Russian and foreign experience of legal regulation and doctrinal understanding of the problems of medical nanorobotics (by the examples of the USA, Japan, Europe, China) was considered.Scientific novelty: under the lack of interdisciplinary research, an attempt was made to comprehensively consider the concept of a medical nanorobot in a technological, legal and communicative way (“human robot” on a nanoscale) based on the advanced scientific research that defines the foundations of the future nanorobotic law. It is recommended to supplement the synergetic development of biomedical and related technologies, reflected in the models of robot law and robot ethics, with relatively independent concepts of nanorobot law and nanorobot ethics.Practical significance: based on the analysis of the legal regulation system in force in Russia and abroad, mechanisms for improving domestic legislation were identified, including taking into account the achievements of juridical crowdsourcing. Within the framework of socio-humanitarian issues, a contribution to the development of legal, sociological, and psychological science is formed. A scientific and methodological basis was prepared for further legal research and law-making activities in the field of medical nanorobotics.
Acid recycling via cation exchange membranes (CEMs) has attracted considerable attention from traditional industries and advanced manufacturing because of the economic and environmental advantages. However, current polymeric CEMs merely have constant ion channels by the fixed groups in the matrix and lack the synergy of bi‐functional sites. Herein, a series of dibenzo‐18‐crown‐6 (DB18C6) functionalized sulfonated poly(biphenyl alkylene) membranes is reported. The resultant membranes form phase separation and ordered ion channels by the electrostatic interaction between DB18C6‐H⁺ complexes and the SO3⁻ anionic sites, constructing a low‐swelling synergistic hydrophilic network. The prepared membranes have high proton permeation rates of 2.98‐4.85 mol m⁻² h‐1 and extremely low ferrous ion permeabilities, leading to a high H⁺/Fe²⁺ selectivity of ≈3153 at the current density of 10 mA cm‐2, which is one order of magnitude higher than the commercial and previously reported membranes via the electrodialysis. These results provide strategies for designing bi‐functional ion exchange membranes for selective ion transport via utilizing crown ether/cation complexes.
Selective transmembrane transport of chloride over competing proton or hydroxide transport is key for the therapeutic application of anionophores, but remains a significant challenge. Current approaches rely on enhancing chloride anion encapsulation within synthetic anionophores. Here we report the first example of a halogen bonding ion relay in which transport is facilitated by the exchange of ions between lipid-anchored receptors on opposite sides of the membrane. The system exhibits non-protonophoric chloride selectivity, uniquely arising from the lower kinetic barrier to chloride exchange between transporters within the membrane, compared to hydroxide, with selectivity maintained across membranes with different hydrophobic thicknesses. In contrast, we demonstrate that for a range of mobile carriers with known high chloride over hydroxide/proton selectivity, the discrimination is strongly dependent on membrane thickness. These results demonstrate that the selectivity of non-protonophoric mobile carriers does not arise from ion binding discrimination at the interface, but rather through a kinetic bias in transport rates, arising from differing membrane translocation rates of the anion-transporter complexes.
A bistable [2]rotaxane based on dibenzylammonium (DBA⁺)/methyl triazolium (MTA⁺) stations and [23]crown ether (X23C7) wheel component has been obtained in excellent yield. The crown ether X23C7 predominantly occupies the DBA⁺ station, in the bistable [2]rotaxane. On addition of the base, the crown ether X23C7 shuttles across to the MTA⁺ station. Acid treatment led to the restoration of X23C7 back to the DBA⁺ station. Due to this reversibility, a pH‐responsive molecular switch has been obtained. This is the first example of a [23]crown ether, a smaller analogue of [24]crown ether, exhibiting shuttling motion in any crown ether‐based mechanically interlocked molecules.
The formation of interlocked structures, such as rotaxane and catenane, enables noncovalent conjugations. We previously confirmed that the chemically cyclized pseudorotaxane-forming oligodeoxynucleotides (prfODNs) with double-tailed parts formed a pseudorotaxane structure with the target DNA and RNA via the slipping process. Here, we report the one-step synthesis of cyclized prfODNs from alkyne-modified ODNs, after which we investigated the properties and mechanism of the slipping process and performed noncovalent RNA labeling with prfODNs. Additionally, the catenane structure was formed by the combination of pseudorotaxane formation with a 5'-end-phosphorylated RNA and enzymatic ligation. The newly synthesized prfODN represents a new tool for achieving the noncovalent conjugation of various functional moieties to RNAs.
Centered around a single phenylalanine residue amidated to have a 15-crown-5 unit at its N-terminus and a straight alkyl chain at its C-terminus, a simple tuning in alkyl chain length...
We demonstrate self-healing of the shuttling dynamics of a molecular machine operating by negative feedback. When zinc(II) was added to the copper(I)-loaded [2]rotaxane shuttle [Cu(R)]+, copper(I) was replaced, thereby generating the static zinc(II)-loaded [2]rotaxane [Zn(R)]2+. Loss of the dynamics was accompanied by a fluorescence enhancement at λ = 364 nm. Notably, the released copper(I) ions catalyzed the formation of a bis-triazole ligand, which selectively captured zinc(II). As a result, the copper(I) was restored in the rotaxane, and the dynamic shuttling motion of [Cu(R)]+ was regained. The healing was conveniently followed by diagnostic fluorescence changes.
The unidirectional rotation of chemically crosslinked light‐driven molecular motors is shown to progressively shift the swelling equilibrium of hydrogels. The concentration of molecular motors and the initial strand density of the polymer network are key parameters to modulate the macroscopic contraction of the material, and both parameters can be tuned using polymer chains of different molecular weights. These findings led to the design of optimized hydrogels revealing a half‐time contraction of approximately 5 min. Furthermore, under inhomogeneous stimulation, the local contraction event was exploited to design useful bending actuators with an energy output 400 times higher than for previously reported self‐assembled systems involving rotary motors. In the present configuration, we measure that a single molecular motor can lift up loads of 200 times its own molecular weight.
The use of cucurbit[n]urils to control the photochemical reactions of styrylpyridine salts has become a new strategy in supramolecular chemistry. In an aqueous solution, styrylpyridine derivatives (CHP) can form supramolecular...
Switching between the formation/dissociation of rotaxanes is important to control the function of various types of rotaxane‐based materials. We have developed a convenient and simple strategy, the so‐called “accelerator addition”, to make a static rotaxane dynamic without apparently affecting the chemical structure. As an interlocked molecule that enables tuning of the formation/dissociation speed, a metallorotaxane was quantitatively generated by the complexation of a triptycene‐based dumbbell‐shaped mononuclear complex, [PdL2]²⁺ (L=2,3‐diaminotriptycene), with 27C9. As a result of the inertness of the Pd²⁺‐based coordination structure, the metallorotaxane was slowly formed (the static state). This rotaxane formation was accelerated 27 times simply by adding Br⁻ as an accelerator (the dynamic state). A similar drastic acceleration was also demonstrated during the dissociation process when Cs⁺ was added to the metallorotaxane to form the free axle [PdL2]²⁺ and the 27C9‐Cs⁺ complex.
Movement is one of the central attributes of life, and a key feature in many technological processes. While artificial motion is typically provided by macroscopic engines powered by internal combustion or electrical energy, movement in living organisms is produced by machines and motors of molecular size that typically exploit the energy of chemical fuels at ambient temperature to generate forces and ultimately execute functions. The progress in several areas of chemistry, together with an improved understanding of biomolecular machines, has led to the development of a large variety of wholly synthetic molecular machines. These systems have the potential to bring about radical innovations in several areas of technology and medicine. In this Minireview, we discuss, with the help of a few examples, the multidisciplinary aspects of research on artificial molecular machines and highlight its translational character.
Nature's molecular machines are a constant source of inspiration to the chemist. Many of these molecular machines function within lipid membranes, allowing them to exploit potential gradients between spatially close, but chemically distinct environments to fuel their work cycle. Indeed, the realisation of such principles in synthetic transmembrane systems remains a tantalising goal. This tutorial review opens by highlighting seminal examples of synthetic molecular machines. We illustrate the importance of surfaces for facilitating the extraction of work from molecular switches and motors. We chart the development of man-made transmembrane systems; from passive to machine-like stimuli-responsive channels, to fully autonomous transmembrane molecular machines. Finally, we highlight higher-order compartmentalised systems that exhibit emergent properties. We suggest that such higher-order architectures could serve as platforms for sophisticated devices that co-ordinate the activity of numerous transmembrane molecular machines.
New approaches to the transmembrane transport of anions are discussed in this review. Advances in the design of small molecule anion carriers are reviewed in addition to advances in the design of synthetic anion channels. The application of anion transporters to the potential future treatment of disease is discussed in the context of recent findings on the selectivity of anion transporters.
Nature's molecular machines are a constant source of inspiration to the chemist. Many of these molecular machines function within lipid membranes, allowing them to exploit potential gradients between spatially close, but chemically distinct environments to fuel their work cycle. Indeed, the realisation of such principles in synthetic transmembrane systems remains a tantalising goal. This tutorial review opens by highlighting seminal examples of synthetic molecular machines. We illustrate the importance of surfaces for facilitating the extraction of work from molecular switches and motors. We chart the development of man-made transmembrane systems; from passive to machine-like stimuli-responsive channels, to fully autonomous transmembrane molecular machines. Finally, we highlight higher-order compartmentalised systems that exhibit emergent properties. We suggest that such higher-order architectures could serve as platforms for sophisticated devices that co-ordinate the activity of numerous transmembrane molecular machines.
The synthetic biology toolbox lacks extendable, conformationally controllable yet easy-to-synthesize building blocks that are long enough to span membranes. To meet this need, an iterative synthesis of α-aminoisobutyric acid (Aib) oligomers was used to create a library of homologous rigid-rod 310-helical foldamers, which have incrementally increasing lengths and functionalizable N- and C-termini. This library was used to probe the interrelationship of foldamer length, self-association strength and ionophoric ability, which is poorly understood. Although foldamer self-association in non-polar chloroform increased with length, with a ~14-fold increase in dimerization constant from Aib6 to Aib11, ionophoric activity in bilayers showed a stronger length dependence, with the observed rate constant for Aib11 ~70-fold greater than that of Aib6. The strongest ionophoric activity was observed for foldamers with >10 Aib residues, which have end-to-end distances greater than the hydrophobic width of the bilayers used (~2.8 nm); X-ray crystallography showed that Aib11 is 2.93 nm long. These studies suggest that being long enough to span to the membrane is more important for good ionophoric activity than strong self-association in the bilayer. Planar bilayer conductance measurements showed that Aib11 and Aib13, but not Aib7, could form pores. This pore-forming behavior is strong evidence that Aibm (m ≥ 10) building blocks can span bilayers.
Mechanically interlocked and entangled molecular architectures represent one of the elaborate topological superstructures engineered at a molecular resolution. Here we report a methodology for fabricating mechanically selflocked molecules (MSMs) through highly efficient one-step amidation of a pseudorotaxane derived from dual functionalized pillar[5]arene (P[5]A) threaded by α,ω-diaminoalkane (DA-n; n=3-12). The monomeric and dimeric pseudo[1]catenanes thus obtained, which are inherently chiral due to the topology of P[5]A used, were isolated and fully characterized by NMR and circular dichroism spectroscopy, X-ray crystallography and DFT calculations. Of particular interest, the dimeric pseudo[1]catenane, named 'gemini-catenane', contained stereoisomeric meso-erythro and dl-threo isomers, in which two P[5]A moieties are threaded by two DA-n chains in topologically different patterns. This access to chiral pseudo[1]catenanes and gemini-catenanes will greatly promote the practical use of such sophisticated chiral architectures in supramolecular and materials science and technology.
Carrier proteins consume fuel in order to pump ions or molecules across cell membranes, creating concentration gradients. Their control over diffusion pathways, effected entirely through noncovalent bonding interactions, has inspired chemists to devise artificial systems that mimic their function. Here, we report a wholly artificial compound that acts on small molecules to create a gradient in their local concentration. It does so by using redox energy and precisely organized noncovalent bonding interactions to pump positively charged rings from solution and ensnare them around an oligomethylene chain, as part of a kinetically trapped entanglement. A redox-active viologen unit at the heart of a dumbbell-shaped molecular pump plays a dual role, first attracting and then repelling the rings during redox cycling, thereby enacting a flashing energy ratchet mechanism with a minimalistic design. Our artificial molecular pump performs work repetitively for two cycles of operation and drives rings away from equilibrium toward a higher local concentration.
Biomolecular motors convert energy into directed motion and operate away from thermal equilibrium. The development of dynamic chemical systems that exploit dissipative (non-equilibrium) processes is a challenge in supramolecular chemistry and a premise for the realization of artificial nanoscale motors. Here, we report the relative unidirectional transit of a non-symmetric molecular axle through a macrocycle powered solely by light. The molecular machine rectifies Brownian fluctuations by energy and information ratchet mechanisms and can repeat its working cycle under photostationary conditions. The system epitomizes the conceptual and practical elements forming the basis of autonomous light-powered directed motion with a minimalist molecular design.
Periplasmic flagella are essential for the distinctive morphology, motility, and infectious life cycle of the Lyme disease spirochete Borrelia burgdorferi. In this study, we genetically trapped intermediates in flagellar assembly and determined the 3D structures of the intermediates to 4-nm resolution by cryoelectron tomography. We provide structural evidence that secretion of rod substrates triggers remodeling of the central channel in the flagellar secretion apparatus from a closed to an open conformation. This open channel then serves as both a gateway and a template for flagellar rod assembly. The individual proteins assemble sequentially to form a modular rod. The hook cap initiates hook assembly on completion of the rod, and the filament cap facilitates filament assembly after formation of the mature hook. Cryoelectron tomography and mutational analysis thus combine synergistically to provide a unique structural blueprint of the assembly process of this intricate molecular machine in intact cells.
We report the synthesis and assembly of umbrella-rotaxanes with transmembrane transport properties. We describe their amphomorphism and validate their ability to penetrate and cross phospholipid bilayers. Furthermore we present the strategy to release the macrocyclic compound by enzymatic cleavage inside egg yolk phosphatidylcholine (EYPC) liposomes.
Ribosomal Rotaxane?
The ribosome is an extraordinarily sophisticated molecular machine, assembling amino acids into proteins based on the precise sequence dictated by messenger RNA. Lewandowski et al. (p. 189 ) have now taken a step toward the preparation of a stripped-down synthetic ribosome analog. Their machine comprises a rotaxane—a ring threaded on a rod—in which the ring bears a pendant thiol that can pluck amino acids off the rod; the terminal nitrogen then wraps around to form a peptide bond and liberate the thiol for further reaction. The system was able to link three amino acids in order from the preassembled rod.
Many cellular processes are carried out by molecular 'machines'-assemblies of multiple differentiated proteins that physically interact to execute biological functions. Despite much speculation, strong evidence of the mechanisms by which these assemblies evolved is lacking. Here we use ancestral gene resurrection and manipulative genetic experiments to determine how the complexity of an essential molecular machine--the hexameric transmembrane ring of the eukaryotic V-ATPase proton pump--increased hundreds of millions of years ago. We show that the ring of Fungi, which is composed of three paralogous proteins, evolved from a more ancient two-paralogue complex because of a gene duplication that was followed by loss in each daughter copy of specific interfaces by which it interacts with other ring proteins. These losses were complementary, so both copies became obligate components with restricted spatial roles in the complex. Reintroducing a single historical mutation from each paralogue lineage into the resurrected ancestral proteins is sufficient to recapitulate their asymmetric degeneration and trigger the requirement for the more elaborate three-component ring. Our experiments show that increased complexity in an essential molecular machine evolved because of simple, high-probability evolutionary processes, without the apparent evolution of novel functions. They point to a plausible mechanism for the evolution of complexity in other multi-paralogue protein complexes.
Life implies movement. Most forms of movement in the living world are powered by tiny protein machines known as molecular motors. Among the best known are motors that use sophisticated intramolecular amplification mechanisms to take nanometre steps along protein tracks in the cytoplasm. These motors transport a wide variety of cargo, power cell locomotion, drive cell division and, when combined in large ensembles, allow organisms to move. Motor defects can lead to severe diseases or may even be lethal. Basic principles of motor design and mechanism have now been derived, and an understanding of their complex cellular roles is emerging.
Nanomachines of the future will require molecular-scale motors that can perform work and collectively induce controlled motion of much larger objects. We have designed a synthetic, light-driven molecular motor that is embedded in a liquid-crystal film and can rotate objects placed on the film that exceed the size of the motor molecule by a factor of 10,000. The changes in shape of the motor during the rotary steps cause a remarkable rotational reorganization of the liquid-crystal film and its surface relief, which ultimately causes the rotation of submillimetre-sized particles on the film.
We describe here a unique family of pore-forming anion-transporting peptides, possessing a single-amino-acid-derived peptidic backbone that is the shortest among natural and synthetic pore-forming peptides. These monopeptides with built-in H-bonding capacity self-assemble into an H-bonded 1D columnar structure, presenting three types of exteriorly arranged hydrophobic side chains that closely mimic the overall topology of an -helix. Dynamic interactions among these side chains and membrane lipids proceed in a way likely similar to how -helix bundle is formed. This subsequently enables oligomerization of these rod-like structures to form ring-shaped ensembles of varying sizes with a pore size of smaller than 1.0 nm in diameter but sufficiently large for transporting anions across the membrane. The intrinsic high modularity in the backbone further allows rapid tuning in side chains for combinatorial optimization of channel’s ion transport activity, culminating in the discovery of an exceptionally active anion-transporting monopeptide 6L10 with an EC50 of 0.10 uM for nitrate anions
A unimolecular ion channel was optimized by functionalization a new type of rigid-rod oligomers. The macrocycle pendant endows chloride selectivity and the fluorescent feature and suitable length of the rod...
Acid fuels the motion of a threaded ring
A central goal in the construction of molecular-scale machines is the efficient achievement of one-way motion. Erbas-Cakmak et al. developed a class of machines that transmit pH changes into the two-stage guided motion of molecular rings threaded on a linear or cyclic axle. The design relies on temporary blocking groups and landing sites along the axle that toggle between active and passive states in response to acid or base. Trichloroacetic acid initiates the first stage of motion until it is decomposed by base in the solution, spurring the second phase.
Science , this issue p. 340
We describe here a modularly tunable molecular strategy for construction and combinatorial optimization of highly efficient K+-selective channels. In our strategy, highly robust supramolecular H-bonded 1D ensemble was used to order the appended crown ethers in such a way that they roughly stack on top of each other to form a channel for facilitated ion transport across the membrane. Among 15 channels that all prefer K+ over Na+ ions, channel molecule 5F8 shows the most pronounced optimum for K+ while disfavoring all other biologically important cations (e.g., Na+, Ca2+ and Mg2+). With a K+/Na+ selectivity of 9.8 and an EC50 value of 6.2 M for K+ ion, 5F8 is clearly among the best synthetic potassium channels developed over the past decades.
To a large extent, the field of "molecular machines" started after several groups were able to prepare, reasonably easily, interlocking ring compounds (named catenanes for compounds consisting of interlocking rings and rotaxanes for rings threaded by molecular filaments or axes). Important families of molecular machines not belonging to the interlocking world were also designed, prepared, and studied but, for most of them, their elaboration was more recent than that of catenanes or rotaxanes. Since the creation of interlocking ring molecules is so important in relation to the molecular machinery area, we will start with this aspect of our work. The second part will naturally be devoted to the dynamic properties of such systems and to the compounds for which motions can be directed in a controlled manner from the outside, that is, molecular machines. We will restrict our discussion to a very limited number of examples which we consider as particularly representative of the field.
Motor proteins are nature's solution for directing movement at the molecular level. The field of artificial molecular motors takes inspiration from these tiny but powerful machines. Although directional motion on the nanoscale performed by synthetic molecular machines is a relatively new development, significant advances have been made. In this review an overview is given of the principal designs of artificial molecular motors and their modes of operation. Although synthetic molecular motors have also found widespread application as (multistate) switches, we focus on the control of directional movement, both at the molecular scale and at larger magnitudes. We identify some key challenges remaining in the field.
In mechanically interlocked compounds, such as rotaxanes and catenanes, the molecules are held together by mechanical rather than chemical bonds. These compounds can be engineered to have several well-defined mechanical states by incorporating recognition sites between the different components. The rates of the transitions between the recognition sites can be controlled by introducing steric “speed bumps” or electrostatically switchable gates. A mechanism for the absorption of energy can also be included by adding photoactive, catalytically active, or redox-active recognition sites, or even charges and dipoles. At equilibrium, these Mechanically Interlocked Molecules (MIMs) undergo thermally activated transitions continuously between their different mechanical states where every transition is as likely as its microscopic reverse. External energy, for example, light, external modulation of the chemical and/or physical environment or catalysis of an exergonic reaction, drives the system away from equilibrium. The absorption of energy from these processes can be used to favour some, and suppress other, transitions so that completion of a mechanical cycle in a direction in which work is done on the environment – the requisite of a molecular machine – is more likely than completion in a direction in which work is absorbed from the environment. In this Tutorial Review, we discuss the different design principles by which molecular machines can be engineered to use different sources of energy to carry out self-organization and the performance of work in their environments.
A series of six [2]rotaxane molecular shuttles was designed which contain an axle with a benzo-bis(imidazole) core (in either a neutral or dicationic form) and a single 24-membered, crown ether wheel (24C6, B24C6, or DMB24C6), and the shuttling rates of the ring along the axle were determined. The charged versions showed much slower shuttling rates as a result of the increase in noncovalent interactions between the axle and wheel. The [2]rotaxane with a B24C6 wheel shows a difference in fluorescence between the charged and neutral species, while the [2]rotaxane with a DMB24C6 wheel exhibits a difference in color between the charged and neutral compounds. These changes in optical properties can be attributed to the structural differences in the co-conformations of the [2]rotaxane as they adapt to the changes in acid/base chemistry. This allowed the relative rate of the translational motion of a molecular shuttle to be determined by observation of a simple optical probe.
Perturbations in cellular chloride concentrations can affect cellular pH, autophagy and lead to the onset of apoptosis. With this in mind synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in the lysosomal pH which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis.
Despite the great interest in the artificial ion channel design, only a small number of channel forming molecules are currently available for addressing challenging problems, particularly in the biological systems. Recent advances on chloride-mediated cell-death, aided by synthetic ion carriers, endorsed us the development of chloride selective supramolecular ion channels. The present work describes vicinal diols, tethered to a rigid 1,3-diethynylbenzene core, as pivotal moieties for the barrel-rosette ion channel formation, and activity of such channels were tuned by controlling the lipophilicity of designed monomers. Selective transport of chloride ions via an antiport mechanism and channel formation in the lipid bilayer membranes were confirmed for the most active molecule. A theoretical model of the supramolecular barrel-rosette, favored by a network of intermolecular hydrogen bonding, has been proposed. The artificial ion channel-mediated transport of chloride into cells and subsequent disruption of cellular ionic homeostasis were evident. Perturbation of chloride homeostasis in cell instigates cell death by inducing caspase-mediated intrinsic pathway of apoptosis.
Three unimolecular peptide channels have been designed and prepared by using the β-helical conformation of gramicidin A (gA). The new peptides bear one to three NH3+ groups at the N-end and one to three CO2− groups at the C-end. These zwitterionic peptides were inserted into lipid bilayers in an orientation-selective manner. Conductance experiments on planar lipid bilayers showed that this orientation bias could lead to observable directional K+ transport under multi-channel conditions. This directional transport behavior can further cause the generation of a current across a planar bilayer without applying a voltage. More importantly, in vesicles with identical external and internal KCl concentrations, the channels can pump K+ across the lipid bilayer and cause a membrane potential.
Membrane channels span the cellular lipid bilayers to transport ions and molecules into cells with sophisticated properties including high efficiency and selectivity. It is of particular biological importance in developing biomimetic transmembrane channels with unique functions by means of chemically synthetic strategies. An artificial unimolecular transmembrane channel using pore-containing helical macromolecules is reported. The self-folding, shape-persistent, pore-containing helical macromolecules are able to span the lipid bilayer, and thus result in extraordinary channel stability and high transporting efficiency for protons and cations. The lifetime of this artificial unimolecular channel in the lipid bilayer membrane is impressively long, rivaling those of natural protein channels. Natural channel mimics designed by helically folded polymeric scaffolds will display robust and versatile transport-related properties at single-molecule level.
Modern-day factory assembly lines often feature robots that pick up, reposition and connect components in a programmed manner. The idea of manipulating molecular fragments in a similar way has to date only been explored using biological building blocks (specifically DNA). Here, we report on a wholly artificial small-molecule robotic arm capable of selectively transporting a molecular cargo in either direction between two spatially distinct, chemically similar, sites on a molecular platform. The arm picks up/releases a 3-mercaptopropanehydrazide cargo by formation/breakage of a disulfide bond, while dynamic hydrazone chemistry controls the cargo binding to the platform. Transport is controlled by selectively inducing conformational and configurational changes within an embedded hydrazone rotary switch that steers the robotic arm. In a three-stage operation, 79-85% of 3-mercaptopropanehydrazide molecules are transported in either (chosen) direction between the two platform sites, without the cargo at any time fully dissociating from the machine nor exchanging with other molecules in the bulk.
Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-(p-nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis.
Twelve novel bis- or tris(macrocyclic) compounds have been designed as models for cation-conducting channels that function in phospholipid bilayer vesicle membranes. In general, the channel model systems have the structure ''sidearm-crown-spacer-crown-spacer-crown-sidearm'', although certain features have been altered from compound to compound to assess the structure-activity relationship. Two additional compounds have been prepared exclusively as controls. The ionophores have been incorporated into the membranes either by warming the compound with the preformed vesicle or by incorporation during vesicle formation. The two methods gave identical results within experimental error. Cation flux was assessed by two different analytical methods. In one case, the fluorescent dye pyranine was encapsulated within vesicles containing ionophore. Proton transport was then monitored by changes in dye fluorescence with time following an acid pulse. Ionophoretic activity far most of the compounds was studied using a dynamic NMR method in which the flux rate of Na-23(+) through the bilayer was monitored. All NMR studies were done in conjunction with gramicidin as a control to minimize experimental variations from run to run. Several of the synthetic ionophores showed cation conduction of as much as 40% of the activity of gramicidin. Apparently, small structural changes significantly altered flux rates and two known carriers closely related to the channel formers failed to exhibit measurable transport under comparable conditions.
The scientific review highlights a selection of important accomplishments of photoresponsive host-guest functional systems, in particular, to demonstrate how light is used to realize the controllable capture and release of guest molecules from host molecules. It focuses on the examples of how to construct a photoresponsive mechanically interlocked molecule to realize light-induced mechanical motion by taking advantage of the well-established host-guest interactions. Emphasis is given to photoresponsive supramolecular polymers and surface-mounted host-guest systems.
Artificial anion selective ion channels with single-file multiple anion-recognition sites are rare. Here, we have designed, by hypothesis, a small molecule that self-organizes to form a barrel rosette ion channel in the lipid membrane environment. Being amphiphilic in nature, this molecule forms nanotubes through intermolecular hydrogen bond formation, while its hydrophobic counterpart is stabilized by hydrophobic interactions in the membrane. The anion selectivity of the channel was investigated by fluorescence-based vesicle assay and planar bilayer conductance measurements. The ion transport by a modified hopping mechanism was demonstrated by molecular dynamics (MD) simulation studies.
Over the last two decades, calix[4]pyrroles have attracted considerable attention as molecular containers. Used in this capacity, they have been exploited as strong and selective receptors and as extractants for both anions and ion pairs. More recently, calix[4]pyrroles have found application as carriers, systems capable of transporting ions and ion pairs across lipophilic membranes. The use of calix[4]pyrroles as building blocks for the preparation of stimulus-responsive material has also been demonstrated. In this latter context, as well as others, the conformational switching, from 1,3-alternate to cone upon anion binding has been exploited to control both structure and substrate binding. In this Review, we describe recent results involving the use of calix[4]pyrrole systems for ion transport. Also summarised is work devoted to the formation of higher order supramolecular aggregates and studies of their response to external stimuli. Taken together, these examples serve to highlight new uses of calix[4]pyrroles as molecular containers.
A general synthesis of triazolium-containing [2]rotaxanes, which could not be accessed by other methods, is reported. It is based on a sequential strategy starting from a well-designed macrocycle transporter which contains a template for dibenzo-24-crown-8 and a N-hydroxysuccinimide (NHS) moiety. The sequence is: 1) synthesis by slippage of a [2]rotaxane building-block; 2) its elongation at its NHS end; 3) the delivery of the macrocycle to the elongated part of the axle by an induced translational motion; 4) the contraction process to yield the targeted [2]rotaxane and recycle the initial transporter.
Light-regulated ion channel-transport across lipid bilayers was realized using structurally simple azobenzene-based amphiphilic small molecules. UV or visible irradiation triggers molecular photoisomerization, which induces structural and membrane affinity changes in self-assembled channels, thus resulting in light-regulated ion transmembrane transport.
The authors report the parameters for a new generic force field, DREIDING, that they find useful for predicting structures and dynamics of organic, biological, and main-group inorganic molecules. The philosophy in DREIDING is to use general force constants and geometry parameters based on simple hybridization considerations rather than individual force constants and geometric parameters that depend on the particular combination of atoms involved in the bond, angle, or torsion terms. Thus all bond distances are derived from atomic radii, and there is only one force constant each for bonds, angles, and inversions and only six different values for torsional barriers. Parameters are defined for all possible combinations of atoms and new atoms can be added to the force field rather simply. This paper reports the parameters for the nonmetallic main-group elements (B, C, N, O, F columns for the C, Si, Ge, and Sn rows) plus H and a few metals (Na, Ca, Zn, Fe). The accuracy of the DREIDING force field is tested by comparing with (i) 76 accurately determined crystal structures of organic compounds involving H, C, N, O, F, P, S, Cl, and Br, (ii) rotational barriers of a number of molecules, and (iii) relative conformational energies and barriers of a number of molecules. The authors find excellent results for these systems.
Modern channel proteins are complex in structure and marvelous in function. The earliest channels cannot possibly have been so complex but they must have functioned at some modest level. Synthetic chemists have designed a variety of novel structures with the goal of creating a mimic of channel function that is complex enough to function in a bilayer but simple enough to be understood, dissected, and modified. These synthetic model systems are the subject of this article.
In various cellular membrane systems, vacuolar ATPases (V-ATPases) function as proton pumps, which are involved in many processes such as bone resorption and cancer metastasis, and these membrane proteins represent attractive drug targets for osteoporosis and cancer. The hydrophilic V(1) portion is known as a rotary motor, in which a central axis DF complex rotates inside a hexagonally arranged catalytic A(3)B(3) complex using ATP hydrolysis energy, but the molecular mechanism is not well defined owing to a lack of high-resolution structural information. We previously reported on the in vitro expression, purification and reconstitution of Enterococcus hirae V(1)-ATPase from the A(3)B(3) and DF complexes. Here we report the asymmetric structures of the nucleotide-free (2.8 Å) and nucleotide-bound (3.4 Å) A(3)B(3) complex that demonstrate conformational changes induced by nucleotide binding, suggesting a binding order in the right-handed rotational orientation in a cooperative manner. The crystal structures of the nucleotide-free (2.2 Å) and nucleotide-bound (2.7 Å) V(1)-ATPase are also reported. The more tightly packed nucleotide-binding site seems to be induced by DF binding, and ATP hydrolysis seems to be stimulated by the approach of a conserved arginine residue. To our knowledge, these asymmetric structures represent the first high-resolution view of the rotational mechanism of V(1)-ATPase.
The synthesis and characterization of a dissymmetric bis-macrocyclic bolaamphiphile ion channel is described. Bilayer-clamp experiments give rectified macroscopic current−voltage responses in which current is carried only at cis-negative potentials. Voltage and orientation-dependent irregular single-channel activity is also observed. Partial protonation of the carboxylate headgroups of the bolaamphiphile results in long-lived single channels with additional shorter-lived states of higher conductance. Single channels are also stabilized in the presence of barium cations. Vesicle experiments establish that transport activity is strongly cation- and concentration-dependent, suggesting the formation of aggregates. The voltage-gating process apparently involves the interaction of the applied potential with the molecular dipole of the bolaamphiphile which stabilizes an active aggregate.
IntroductionMethods
CharacteristicsStructural StudiesConcluding RemarksAcknowledgmentReferences
The formation and exchange processes of imines of benzaldehyde have been studied, showing that the former has features of for dynamic covalent chemistry, displaying high efficiency and fast rates. The monoimines formed with aliphatic a,alpha,omega-diamines display an internal exchange process of self-transimination type, inducing a local motion of either "stepping-in-place" or "single-step" type by bond interchange, whose rate decreases rapidly with the distance of the terminal amino groups. Control of the speed of the process over a wide range may be achieved by substituents, solvent composition, and temperature. These monoimines also undergo intermolecular exchange, thus merging motional and constitutional covalent behavior within the same molecule. With polyamines, the monoimines formed execute internal motions that have been characterized by extensive one-dimensional, two-dimensional, and EXSY proton NMR studies. In particular, with linear polyamines, nondirectional displacement occurs by shifting of the aldehyde residue along the polyamine chain serving as molecular track. lmines thus behave as simple prototypes of systems displaying relative motions of molecular moieties, a subject of high current interest in the investigation of synthetic and biological molecular motors. The motional processes described are of dynamic covalent nature and take place without change in molecular constitution. They thus represent a category of dynamic covalent motions, resulting from reversible covalent bond formation and dissociation. They extend dynamic covalent chemistry into the area of molecular motions. A major further step will be to achieve control of directionality. The results reported here for imines open wide perspectives, together with other chemical groups, for the implementation of such features in multifunctional molecules toward the design of molecular devices presenting a complex combination of motional and constitutional dynamic behaviors.
Hydrazide-appended pillar[5]arene derivatives have been synthesized. X-ray crystal structure analysis and (1)H NMR studies revealed that the molecules adopt unique tubular conformations. Inserting the molecules into the lipid membranes of vesicles leads to the transport of water through the channels produced by single molecules, as supported by dynamic light scattering and cryo-SEM experiments. The channels exhibit the transport activity at a very low channel to lipid ratio (0.027 mol %), and a water permeability of 8.6 × 10(-10) cm s(-1) is realized. In addition, like natural water channel proteins, the artificial systems also block the transport of protons.
Synthetic ion channels have been known for nearly three decades, but it is only in the past decade that analysis of the currents these ionic conductors carry has become a standard technique. A broad range of structural types have been explored and these reports have produced a very diverse collection of ion channel conductance behaviours. In this critical review we describe a notational method to extract salient information from reported ion channel experiments. We use an activity grid to represent quantitative information on conductance and opening duration with a five-level colour code to represent qualitative information on the nature of the conductance-time profile. Analysis of the cumulative dataset suggests that the reported conductance data can reflect the structural features of the compounds prepared, but does also reflect the energetic landscape of the bilayer membrane in which synthetic ion channels function (143 references).
The General Utility Lattice Program (gulp) has been extended to include the ability to simulate polymers and surfaces, as well as adding many other new features, and the current status of the program is fully documented. Both the background theory is described, as well as providing a concise review of some of the previous applications in order to demonstrate the range of its use. Examples are presented of work performed using the new compatibilities of the software, including the calculation of Born effective charges, mechanical properties as a function of applied pressure, calculation of frequency-dependent dielectric data, surface reconstructions of calcite and the performance of a linear-scaling algorithm for bond-order potentials.
A number of synthetic ion channels have been reported in recent years that incorporate unusual or sophisticated design elements. The present work demonstrates that extremely simple compounds can function as ion channels (insert in bilayers, exhibit open-close behavior) if they meet minimum criteria. A simple membrane spanning structure may function as a channel if 1) it possesses polar headgroups (is bolaamphiphilic), 2) possesses a "central relay," and 3) channel function (open-close behavior) must be detected after insertion of the amphiphile directly into the aqueous liposomal or cellular suspension. We show here compounds that are simple spans to which we have given the name "aplosspan" (from the Greek alpha pi lambda omicron sigma + span) that meet these criteria. They are similar to, but simpler than, structures reported in the literatures that incorporate more complex design features.
A technique for investigating the gramicidin-facilitated transport of Na+ ions across lipid bilayers of large unilamellar vesicles under the condition of ionic equilibrium has been developed using a combination of heat incubation of the gramicidin with the vesicles and 23Na-nuclear magnetic resonance (NMR) spectroscopy. Isolation of the two 23Na-NMR signals from the intra- and extravesicular Na+ with the shift reagent, dysprosium (III) tripolyphosphate, allows the equilibrium flux of Na+ through the gramicidin channels to be detected and treated as a two-site exchange process. This study indicates that the transport of Na+ through gramicidin channels is second order with respect to the gramicidin concentration.
Although scientific progress is usually represented as being linear,
it may, in fact, have a cyclical character ? some discoveries may be
forgotten or lost (at least temporarily), and themes may reappear through
the centuries. Consider, for example, the concept of 'molecular machines',
from the exciting phase of research that flourished in the seventeenth century,
to the idea of machines that is at centre stage in modern cell biology.