Ion transport across lipid membranes in biology is controlled by stimuli-responsive membrane channels and molecular machine ion pumps such as ATPases. Here, we report a synthetic molecular ...machine-like ion transport relay, in which transporters on opposite sides of a lipid bilayer membrane facilitate transport by passing ions between them. By incorporating a photo-responsive telescopic arm into the relay design, this process is reversibly controlled in response to irradiation with blue and green light. Transport occurs only in the extended state when the length of the arm is sufficient to pass the anion between transporters located on opposite sides of the membrane. In contrast, the contracted state of the telescopic arm is too short to mediate effective transport. The system acts as a stimuli-responsive ensemble of machine-like components, reminiscent of robotic arms in a factory assembly line, working cooperatively to mediate ion transport. This work points to new prospects for using lipid bilayer membranes as scaffolds for confining, orientating, and controlling the relative positions of molecular machines, thus enabling multiple components to work in concert and opening up new applications in biological contexts.
Lipid bilayer membranes form compartments requisite for life. Interfacing supramolecular systems, including receptors, catalysts, signal transducers and ion transporters, enables the function of the ...membrane to be controlled in artificial and living cellular compartments. In this perspective, we take stock of the current state of the art of this rapidly expanding field, and discuss prospects for the future in both fundamental science and applications in biology and medicine.
This perspective provides an overview of the current state of the art in supramolecular chemistry in lipid bilayer membranes, including receptors, signal transducers, catalysts and transporters, and highlights prospects for the future.
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 machinesmolecular systems in which a nanomechanical motion is exploited for functionhave 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.
This article draws upon responses given by volunteers who work in the Beijing LGBT Centre regarding perceptions of sexual identity, and how Chinese culture affects hidden or open sexual identities of ...Chinese lesbian and gay people in this region. The insights gained from those working carefully to create social change offers an important and original contribution to the field of gay and lesbian studies in China. The findings indicate the volunteers at the Beijing LGBT Centre are frustrated by the lack of acceptance of non‐heterosexual relationships among Chinese culture and society, and by the disregard of lesbian gay and bisexual (LGB) people by the Chinese government. The findings also illustrate stigmatization of homosexuality in China is enacted in structural terms (such as in the lack of policy, legislation and positive endorsement by governmental and socio‐political organizations), public expression (such as negative attitudes, beliefs or reactions towards LGB people) and internalized repression (through fear of stigmatization, and subsequent abuse due to negative societal attitudes and discrimination). Influenced by the Chinese tradition of conforming to group values, the findings from this study show that volunteers at the Beijing LGBT Centre believe LGB people in China are generally hesitant to disclose their sexual identities, and reject the idea that there had been a collective shift in Chinese culture regarding increased acceptance of LGB people. It also finds volunteers at the LGBT Centre in Beijing blame Chinese culture for its lack of acceptance of non‐heterosexual relationships, and state stigmatization of homosexuality in China is due to deep‐rooted cultural homophobia.
A homologous series of azobenzene-derived photo-switchable ion relay transporters is reported. We reveal that both the length and geometry of the relay strongly affect transport rate, allowing the ...relative activity of the
E
and
Z
isomers to be reversed and hence the wavelengths of light used for on and off switching to be exchanged.
A homologous series of photo-switchable relay anion transporters is reported. Length and shape of the relay influences the rate of transport, enabling visible light regulation of activity and tunability of the irradiation wavelength.
Synthetic supramolecular transmembrane anionophores have emerged as promising anticancer chemotherapeutics. However, key to their targeted application is achieving spatiotemporally controlled ...activity. Herein, we report a series of chalcogen-bonding diaryl tellurium-based transporters in which their anion binding potency and anionophoric activity are controlled through reversible redox cycling between Te oxidation states. This unprecedented in situ reversible multistate switching allows for switching between ON and OFF anion transport and is crucially achieved with biomimetic chemical redox couples.
Transmission of chemical information between cells and across lipid bilayer membranes is of profound significance in many biological processes. The design of synthetic signalling systems is a ...critical step towards preparing artificial cells with collective behaviour. Here, we report the first example of a synthetic inter-vesicle signalling system, in which diffusible chemical signals trigger transmembrane ion transport in a manner reminiscent of signalling pathways in biology. The system is derived from novel ortho-nitrobenzyl and BODIPY photo-caged Zn
transporters, in which cation transport is triggered by photo-decaging with UV or red light, respectively. This decaging reaction can be used to trigger the release of the cationophores from a small population of sender vesicles. This in turn triggers the transport of ions across the membrane of a larger population of receiver vesicles, but not across the sender vesicle membrane, leading to overall inter-vesicle signal transduction and amplification.
Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer's disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated ...genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1, APH1B, PTK2B, PILRA and CASS4.
Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat channelopathies. Stimulus‐responsive ...systems that offer spatiotemporally controlled activity for targeted applications remain rare. Here we utilize dynamic hydrogen bonding interactions of a 4,6‐dihydroxy‐isophthalamide core to generate a modular platform enabling access to stimuli‐responsive ion transporters that can be activated in response to a wide variety of external stimuli, including light, redox, and enzymes, with excellent OFF‐ON activation profiles. Alkylation of the two free hydroxyl groups with stimulus‐responsive moieties locks the amide bonds through intramolecular hydrogen bonding and hence makes them unavailable for anion binding and transport. Triggering using a particular stimulus to cleave both cages reverses the hydrogen bonding arrangement, to generate a highly preorganized anion binding cavity for efficient transmembrane transport. Integration of two cages that are responsive to orthogonal stimuli enables multi‐stimuli activation, where both stimuli are required to trigger transport in an AND logic process. Importantly, the strategy provides a facile method to post‐functionalize the highly active transporter core with a variety of stimulus‐responsive moieties for targeted activation with multiple triggers.
A modular platform for accessing stimuli‐responsive anionophores, triggered by multiple stimuli of biological relevance including light, redox, and an esterase, is reported, and accessed via post‐synthetic modification of a dynamic hydrogen bonding anionophore. By utilizing two different cages, a responsive anionophore with AND logic activation, requiring two different stimuli, was achieved.
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 halogen bonding anion relay with Cl
−
> OH
−
selectivity is reported. Selectivity is maintained across lipid membranes of different thicknesses, whereas for selective mobile carriers the discrimination is strongly dependent on membrane thickness.