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The effect of the two‐dimensional glycan display on glycan‐lectin recognition remains poorly understood despite the importance of these interactions in a plethora of cellular processes, in (patho)physiology, as well as its potential for advanced therapeutics. Faced with this challenge we utilized glycodendrimersomes, a type of synthetic vesicles whose membrane mimics the surface of a cell and offers a means to probe the carbohydrate biological activity. These single‐component vesicles were formed by the self‐assembly of sequence‐defined mannose‐Janus dendrimers, which serve as surrogates for glycolipids. Using atomic force microscopy and molecular modeling we demonstrated that even mannose, a monosaccharide, was capable of organizing the sugar moieties into periodic nanoarrays without the need of the formation of liquid‐ordered phases as assumed necessary for rafts. Kinetics studies of Concanavalin A binding revealed that those nanoarrays resulted in a new effective ligand yielding a ten‐fold increase in the kinetic and thermodynamic constant of association., Multivalent interactions mediated by the cellular glycocalix are ubiquitous in biological processes. We utilized glycodendrimersomes, a type of synthetic cell membrane mimic to probe the carbohydrate biological activity towards lectins. We demonstrated that mannose could organize the sugar moieties into periodic nanoarrays resulting in a new effective ligand yielding a ten‐fold increase in the kinetic and thermodynamic constant of association.

This computational study illustrates how modifying the end groups of polymer chains offers a viable strategy to control polymer crystal nucleation in entangled melts. More specifically, altering ch...

The vital functions of cell membranes require their ability to quickly change shape to perform complex tasks such as motion, division, endocytosis, and apoptosis. Membrane curvature in cells is modulated by very complex processes such as changes in lipid composition, the oligomerization of curvature-scaffolding proteins, and the reversible insertion of protein regions that act like wedges in the membrane. But, could much simpler mechanisms support membrane shape transformation? In this work, we demonstrate how the change of amphiphile topology in the bilayer can drive shape transformations of cell membrane models. To tackle this, we have designed and synthesized new types of amphiphiles-Janus dendrimers-that self-assemble into uni-, multilamellar, or smectic-ordered vesicles, named dendrimersomes. We synthesized Janus dendrimers containing a photo-labile bond that upon UV-Vis irradiation cleavage lose a part of the hydrophilic dendron. This leads to a change from a cylindrically to a wedge-shaped amphiphile. The high mobility of these dendrimers allows for the concentration of the wedge-shaped amphiphiles and the generation of transmembrane asymmetries. The concentration of the wedges and their rate of segregation allowed control of the budding and generation of structures such as tubules and high genus vesicles.

The role of geometric frustration of water molecules in the rate of water oxidation in the nanoconfined interlayer of manganese-oxide layered materials (birnessite, buserite) is examined in a well-controlled experiment. Calcium buserite is prepared, and used in a split-batch synthetic protocol to prepare calcium birnessite, sodium buserite, and sodium birnessite, and partially dehydrated sodium birnessite. Thus, four samples are prepared in which features effecting catalytic efficiency (defect density, average manganese oxidation state) are controlled, and the main difference is the degree of hydration of the interlayer (two layers of water in buserites vs. one layer of water in birnessite). Molecular dynamics simulations predict birnessite samples to exhibit geometric water frustration, which facilitates redox catalysis by lowering the Marcus reorganization energy of electron transfer, while buserite samples exhibit traditional intermolecular hydrogen bonding among the two-layer aqeuous region, leading to slower catalytic behavior akin to redox reactions in bulk water. Water oxdiation activity is investigated using chemical and electrochemical techniques, demonstrating and quantifying the role of water frustration in enhancing catalysis. Calculation and experiment demonstrate dehydrated sodium birnessite to be most effective, and calcium buserite the least effective, with a difference in electrocatlytic overpotential of ∼750 mV and a ∼20-fold difference in turnover number.

Unlike metal or semiconductor electrodes, the surface charge resulting from the protonation or deprotonation of insulating mineral oxides is highly localized and heterogeneous in nature. In this work the Stark active C≡N stretch of potassium thiocyanate is used as a molecular probe of the heterogeneity of the interfacial electrostatic potential at the α-Al2O3(0001)/H2O interface. Vibrational sum frequency generation (vSFG) measurements performed in the OH stretching region suggest that thiocyanate species organize interfacial water similarly to halide ions. Changes in the electrostatic potential are then tracked via Stark shifts of the vibrational frequency of the thiocyanate stretch. Our vSFG measurements show that we can simultaneously measure the vSFG response of SCN- ions experiencing charged and neutral surface sites. We assign local potentials of +308 and -154 mV to positively and negatively charged aluminol groups that are present at pH = 4 and pH = 10, respectively. Thiocyanate anions at positively charged surface sites and negatively charged surface sites and those participating in contact ion pairing adopt similar orientations and are oppositely oriented relative to thiocyanate ions near neutral surface sites. All four species followed Langmuir adsorption isotherms. Density functional theory-molecular dynamics (DFT-MD) simulations of SCN- near the neutral α-Al2O3(0001)/H2O interface show that the vSFG response in the C≡N stretch region originates from a SCN-H-O-Al complex, suggesting the surface site specificity of these experiments. To our knowledge this is the first spectroscopic measurement of local potentials associated with a heterogeneously charged surface. The ability to probe the evolution of local charges in situ could provide vital insight into many industrial, electrochemical, and geochemically relevant interfaces.

Spatial distributions are presented that quantitatively capture how polymer properties (e.g., segment alignment, density, and potential energy) vary with distance from nascent polymer crystals (nuclei) in prototypical polyethylene melts. It is revealed that the spatial extent of nuclei and their interfaces is metric-dependent as is the extent to which nucleus interiors are solid-like. As distance from a nucleus increases, some properties, such as density, decay to melt-like behavior more rapidly than polymer segment alignment, indicating that a polymer nucleus resides in a nematic-like droplet. This nematic-like droplet region coincides with enhanced formation of ordered polymer segments that are not part of the nucleus. It is more favorable to find nonconstituent ordered polymer segments near a nucleus than in the surrounding metastable melt, pointing to the possibility of one nucleus inducing the formation of other nuclei. In this vein, there is also a second region of enhanced ordering that lies along the nematic director of a nucleus, but beyond its nematic droplet and fold regions. These results indicate that crystal stacking, a key characteristic of lamellae in semicrystalline polymeric materials, begins to emerge during the earliest stages of polymer crystallization (i.e., crystal nucleation). More generally, the findings of this study provide a conceptual bridge between polymer crystal nucleation under nonflow and flow conditions and are used to rationalize previous results.

Release of cargo molecules from cell-like nanocarriers can be achieved by chemical perturbations, including changes to pH and redox state and via optical modulation of membrane properties. However, little is known about the kinetics or products of vesicle breakdown due to limitations in real-time imaging at nanometer length scales. Using a library of 12 single-single type photocleavable amphiphilic Janus dendrimers, we developed a self-assembling light-responsive dendrimersome vesicle platform. A photocleavable ortho-nitrobenzyl inserted between the hydrophobic and hydrophilic dendrons of amphiphilic Janus dendrimers allowed for photocleavage and disassembly of their supramolecular assemblies. Distinct methods used to self-assemble amphiphilic Janus dendrimers produced either nanometer size small unilamellar vesicles or micron size giant multilamellar and onion-like dendrimersomes. In situ observation of giant photosensitive dendrimersomes via confocal microscopy elucidated rapid morphological transitions that accompany vesicle breakdown upon 405 nm laser illumination. Giant dendrimersomes displayed light-induced cleavage, disassembling and reassembling into much smaller vesicles at millisecond time scales. Additionally, photocleavable vesicles demonstrated rapid release of molecular and macromolecular cargos. These results guided our design of multilamellar particles to photorelease surface-attached proteins, photoinduce cargo recruitment, and photoconvert vesicle morphology. Real-time characterization of the breakdown and reassembly of lamellar structures provides insights on partial cargo retention and informs the design of versatile, optically regulated carriers for applications in nanoscience and synthetic biology.

Electron attachment to DNA by low energy electrons can lead to DNA damage, so a fundamental understanding of how electrons interact with the components of nucleic acids in solution is an open challenge. In solution, low energy electrons can generate presolvated electrons, epre-, which are efficiently scavanged by pyrimidine nucleobases to form transient negative ions, able to relax to either stable valence bound anions or undergo dissociative electron detachment or transfer to other parts of DNA/RNA leading to strand breakages. In order to understand the initial electron attachment dynamics, this paper presents a joint molecular dynamics and high-level electronic structure study into the behavior of the electronic states of the solvated uracil anion. Both the valence π* and nonvalence epre- states of the solvated uracil system are studied, and the effect of the solvent environment and the geometric structure of the uracil core are uncoupled to gain insight into the physical origin of the stabilization of the solvated uracil anion. Solvent reorganization is found to play a dominant role followed by relaxation of the uracil core.

The high anisotropy of polymer-based fibres confers them high tensile strength, but also makes them more vulnerable against non-uniform mechanical loads. This is even more important for Kevlar® fib...

Significance The TRPA1 channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. TRPA1 can be activated by electrophilic compounds via covalent modification or activated by noncovalent agonists via ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we identified a group of noncovalent agonists and used them to explore TRPA1 gating through iterative functional analyses, molecular modeling, and structure–activity relationship studies. We show that TRPA1 possesses an evolutionarily conserved ligand binding site common to other TRP channels. The combination of computational modeling and experimental structure–activity data lays the foundations for rational drug design., The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1–PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving π-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure–activity studies, thereby suggesting strategies for rational drug design.

Purpose To assess whether genotypes at 2 major loci associated with age-related macular degeneration (AMD), complement factor H (CFH), or age-related maculopathy susceptibility 2 (ARMS2), modify the response to oral nutrients for the treatment of AMD in the Age-Related Eye Disease Study 2 (AREDS2). Design Post hoc analysis of a randomized trial. Participants White AREDS2 participants. Methods AREDS2 participants (n = 4203) with bilateral large drusen or late AMD in 1 eye were assigned randomly to lutein and zeaxanthin, omega-3 fatty acids, both, or placebo, and most also received the AREDS supplements. A secondary randomization assessed modified AREDS supplements in 4 treatment arms: lower zinc dosage, omission of β-carotene, both, or no modification. To evaluate the progression to late AMD, fundus photographs were obtained at baseline and annual study visits, and history of treatment for late AMD was obtained at study visits and 6-month interim telephone calls. Participants were genotyped for the single-nucleotide polymorphisms rs1061170 in CFH and rs10490924 in ARMS2. Bivariate frailty models using both eyes were conducted, including a gene–supplement interaction term and adjusting for age, gender, level of education, and smoking status. The main treatment effects, as well as the direct comparison between lutein plus zeaxanthin and β-carotene, were assessed for genotype interaction. Main Outcome Measures The interaction between genotype and the response to AREDS2 supplements regarding progression to late AMD, any geographic atrophy (GA), and neovascular AMD. Results Complete data were available for 2775 eyes without baseline late AMD (1684 participants). The participants (mean age ± standard deviation, 72.1±7.7 years; 58.5% female) were followed up for a median of 5 years. The ARMS2 risk allele was associated significantly with progression to late AMD and neovascular AMD (P = 2.40 × 10–5 and P = 0.002, respectively), but not any GA (P = 0.097). The CFH risk allele was not associated with AMD progression. Genotype did not modify significantly the response to any of the AREDS2 supplements. Conclusions CFH and ARMS2 risk alleles do not modify the response to the AREDS2 nutrient supplements with respect to the progression to late AMD (GA and neovascular AMD).

Significance Lipid vesicles are globular assemblies that compartmentalize, encapsulate, transport, and provide signal transmission and communication between cells. In living systems, these vesicles perform critical functions to sustain life. Biomimetic lipid vesicles, such as liposomes, have been developed as mimics of biological cell membranes and for applications in biotechnology, but they do have specific limitations. Dendrimersomes are vesicles self-assembled from amphiphilic Janus dendrimers. They offer improved stability and versatility over liposomes. These dendrimersomes are extremely efficient at loading hydrophobic small molecules and natural macromolecules including folded proteins, at a level higher than comparable liposomes. Additionally, they can be readily functionalized to enable modular recruitment of proteins and nucleic acids on their periphery., Reconstructing the functions of living cells using nonnatural components is one of the great challenges of natural sciences. Compartmentalization, encapsulation, and surface decoration of globular assemblies, known as vesicles, represent key early steps in the reconstitution of synthetic cells. Here we report that vesicles self-assembled from amphiphilic Janus dendrimers, called dendrimersomes, encapsulate high concentrations of hydrophobic components and do so more efficiently than commercially available stealth liposomes assembled from phospholipid components. Multilayer onion-like dendrimersomes demonstrate a particularly high capacity for loading low-molecular weight compounds and even folded proteins. Coassembly of amphiphilic Janus dendrimers with metal-chelating ligands conjugated to amphiphilic Janus dendrimers generates dendrimersomes that selectively display folded proteins on their periphery in an oriented manner. A modular strategy for tethering nucleic acids to the surface of dendrimersomes is also demonstrated. These findings augment the functional capabilities of dendrimersomes to serve as versatile biological membrane mimics.

Alumina is one of the most abundant minerals and has a wide range of industrial applications, with catalysis as one of the most important. Of particular relevance for catalysis is the structure of the mineral/water interface. In this work, water structure and sodium halide adsorption at the neutral α-alumina(0001)/water interface are investigated using molecular dynamics simulations. This work demonstrates the accuracy of the chosen model of the alumina/water interface and shows that high charge density monovalent ions, such as Na+ and F–, have a strong affinity for the interface due to the specific pattern of alumina surface OH groups, such that the adsorbed ions displace waters that are hydrogen-bonded to the surface in their absence. A significant portion of the driving force for anion adsorption arises from surface bound Na+, which reverse the intrinsic surface dipole field and drive the accumulation of halides at the interface. The resulting electrolytic interfacial structure reorients water molecule...

We present a new model for the calculation of molecular polarizabilities from effective atomic polarizabilities. This model is based on the Thole modified dipole interaction model for molecular polarizabilities, where the total polarizability is computed as a sum of effective atomic polarizabilities modified by dipole-dipole interactions. We extend this model by making the atomic polarizabilities explicit functions of the interatomic distances, scaling them by the radius of the volume an atom occupies in a molecule. We use the SCAN functional to show that this model, denoted TholeL, yields accurate molecular polarizabilities with little dependence on the training set. We also demonstrate that the TholeL model yields accurate polarizabilities for configurations far from the ground state structure for a wide range of molecules. Finally, we show that the TholeL model can be used to generate accurate Raman spectra for water, crystalline urea, and urea in water from ab initio molecular dynamics simulations.

Summary Store-operated calcium release-activated calcium (CRAC) channels mediate a variety of cellular signaling functions. The CRAC channel pore-forming protein, Orai1, is a hexamer arranged with 3-fold symmetry. Despite its importance in moving Ca2+ ions into cells, a detailed mechanistic understanding of Orai1 activation is lacking. Herein, a working model is proposed for the putative open state of Orai from Drosophila melanogaster (dOrai), which involves a “twist-to-open” gating mechanism. The proposed model is supported by energetic, structural, and experimental evidence. Fluorescent imaging demonstrates that each subunit on the intracellular side of the pore is inherently strongly cross-linked, which is important for coupling to STIM1, the pore activator, and graded activation of the Orai1 channel. The proposed model thus paves the way for understanding key aspects of calcium signaling at a molecular level., Graphical Abstract, Highlights • Mechanical coupling within the calcium channel pore is critical for its activation • Molecular modeling could disclose gating mechanism of ion channels at atomic level • The predicted open-state structure of the pore was further confirmed by experiments, Biological Sciences; Molecular Biology; Structural Biology

The lowering of reaction overpotentials is a persistent and universal goal in the development of catalysts for (photo)electrochemistry, which can usually be facilitated by selectively stabilizing one reaction intermediate over another. In this mechanistic study of the oxygen evolution reaction (OER) catalyzed by cobalt-intercalated layered MnO2, we show that confinement effects and local cobalt atomic ordering in the interlayer space can be synergistically used to tune the adsorption energies of O, OH, and OOH reaction intermediates and the scaling relationship between them. In general, the interlayer confinement destabilizes the adsorption of intermediates for the OER, but clustering Co atoms can selectively stabilize the adsorption of OOH in particular. After considering both effects, our model predicts an overpotential of 0.30 V for the Co-intercalated MnO2 catalyzed OER, in excellent agreement with the experimental result of 0.36 V. These new insights explain the enhanced catalytic performance of MnO2 by intercalating atoms and illuminate a route for engineering non-toxic precious-metal-free catalysts through designed layered materials.

Water exchange reactions around ionic solutes are ubiquitous in aqueous solution-phase chemistry. However, the extreme sensitivity of exchange rates to perturbations in the chemistry of an ionic solute is not well understood. We examine water exchange around model ions within the language of dynamic facilitation theory, typically used to describe glassy and other systems with collective, facilitated dynamics. Through the development of a coarse-grained, kinetically-constrained lattice model of water exchange, we show that the timescale for water exchange scales exponentially with the strength of the solute-solvent interactions., Comment: 8 pages, 6 figures

Summary The small 3-O-sulfated galactose head group of sulfatides, an abundant glycosphingolipid class, poses the (sphinx-like) riddle on involvement of glycan bridging by tissue lectins (sugar code). First, synthesis of head group derivatives for functionalization of amphiphilic dendrimers is performed. Aggregation of resulting (biomimetic) vesicles, alone or in combination with lactose, demonstrates bridging by a tissue lectin (galectin-4). Physiologically, this can stabilize glycolipid-rich microdomains (rafts) and associate sulfatide-rich regions with specific glycoproteins. Further testing documents importance of heterobivalency and linker length. Structurally, sulfatide recognition by galectin-8 is shown to involve sphingosine's OH group as substitute for the 3′-hydroxyl of glucose of lactose. These discoveries underscore functionality of this small determinant on biomembranes intracellularly and on the cell surface. Moreover, they provide a role model to examine counterreceptor capacity of more complex glycans of glycosphingolipids and to start their bottom-up glycotope surface programming., Graphical abstract, Highlights • Nanoparticle programming detects sulfatide-(N)-glycan bridging by galectins-4 and -8 • Protein design (linker/domain type) is a switch for aggregation activity • Sphingosine's OH group is involved in contact building with a galectin, Supramolecular Chemistry; Biochemistry; Biophysics

The mechanism of action of quaternary ammonium compound (QAC) antiseptics has long been assumed to be straightforward membrane disruption, although the process of approaching and entering the membrane has little modeling precedent. Furthermore, questions have more recently arisen regarding bacterial resistance mechanisms, and why select classes of QACs (specifically, multicationic QACs) are less prone to resistance. In order to better understand such subtleties, a series of molecular dynamics simulations were utilized to help identify these molecular determinants, directly comparing mono-, bis-, and triscationic QACs in simulated membrane intercalation models. Three distinct membranes were simulated, mimicking the surfaces of Escherichia coli and Staphylococcus aureus, as well as a neutral phospholipid control. By analyzing the resulting trajectories in the form of a timeseries analysis, insight was gleaned regarding the significant steps and interactions involved in the destabilization of phospholipid bilayers within the bacterial membranes. Finally, to more specifically probe the effect of the hydrophobic section of the amphiphile that presumably penetrates the membrane, a series of alkyl- and ester-based biscationic quaternary ammonium compounds were prepared, tested for antimicrobial activity against both Gram-positive and Gram-negative bacteria, and modeled.

This study demonstrates that monodisperse entangled polymer melts crystallize via the formation of nanoscale nascent polymer crystals (i.e., nuclei) that exhibit substantial variability in terms of their constituent crystalline polymer chain segments (stems). More specifically, large-scale coarse-grain molecular simulations are used to quantify the evolution of stem length distributions and their properties during the formation of polymer nuclei in supercooled prototypical polyethylene melts. Stems can adopt a range of lengths within an individual nucleus (e.g., &sim, 1&ndash, 10 nm) while two nuclei of comparable size can have markedly different stem distributions. As such, the attainment of chemically monodisperse polymer specimens is not sufficient to achieve physical uniformity and consistency. Furthermore, stem length distributions and their evolution indicate that polymer crystal nucleation (i.e., the initial emergence of a nascent crystal) is phenomenologically distinct from crystal growth. These results highlight that the tailoring of polymeric materials requires strategies for controlling polymer crystal nucleation and growth at the nanoscale.

Many atomic liquids can form transient covalent bonds reminiscent of those in the corresponding solid states. These directional interactions dictate many important properties of the liquid state, necessitating a quantitative, atomic-scale understanding of bonding in these complex systems. A prototypical example is liquid silicon, wherein transient covalent bonds give rise to local tetrahedral order and consequent non-trivial effects on liquid state thermodynamics and dynamics. To further understand covalent bonding in liquid silicon, and similar liquids, we present an ab initio simulation-based approach for quantifying the structure and dynamics of covalent bonds in condensed phases. Through the examination of structural correlations among silicon nuclei and maximally localized Wannier function centers, we develop a geometric criterion for covalent bonds in liquid Si. We use this to monitor the dynamics of transient covalent bonding in the liquid state and estimate a covalent bond lifetime. We compare covalent bond dynamics to other processes in liquid Si and similar liquids and suggest experiments to measure the covalent bond lifetime., Comment: 6 pages, 4 figures

Sorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD), and a histologic hallmark of SFD is a thick layer of extracellular deposits beneath the retinal pigment epithelium (RPE). Previous studies of SFD patient-induced pluripotent stem cell (iPSC) derived RPE differ as to whether these cultures recapitulate this key clinical feature by forming increased drusenoid deposits. The primary purpose of this study is to examine whether SFD patient-derived iPSC-RPE form basal deposits similar to what is found in affected family member SFD globes and to determine whether SFD iPSC RPE may be more oxidatively stressed. We performed a careful comparison of iPSC RPE from three control individuals, multiple iPSC clones from two SFD patients’ iPSC RPE, and post-mortem eyes of affected SFD family members. We also examined the effect of CRISPR-Cas9 gene correction of the S204C TIMP3 mutation on RPE phenotype. Finally, targeted metabolomics analysis with liquid chromatography and mass spectrometry analysis and stable isotope-labeled metabolite analysis was performed to determine whether SFD RPE are more oxidatively stressed. We found that SFD iPSC-RPE formed significantly more sub-RPE deposits (∼6-90 μm in height) compared to control RPE at 8 weeks. These deposits were similar in composition to the basal laminar drusen found in SFD family member globes by immunofluorescence staining and TEM imaging. S204C TIMP3 correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in significantly reduced basal laminar and sub-RPE calcium deposits. We detected a ∼18-fold increase in TIMP3 accumulation in the extracellular matrix (ECM) of SFD RPE, and targeted metabolomics showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE, suggesting increased ECM turnover. Finally, SFD RPE cells have decreased intracellular reduced glutathione and were found to be more vulnerable to oxidative stress. Our findings suggest that elements of SFD pathology can be demonstrated in culture which may lead to insights into disease mechanisms.

Significance Gram-negative bacterial cells such as Escherichia coli contain a relatively rigid outer membrane, and cross-linked peptidoglycan in their periplasm, giving them the rigidity and stability to survive independently in harsh environments. To dismantle these strong bacterial cell envelopes, enzymatic processes need to be used. In contrast, human cell membranes are much more fragile, making it possible to dismantle them more easily by relatively mild mechanical disruption. Once these membranes are dismantled, they can be coassembled with synthetic phospholipid mimics, named Janus dendrimers, into cell-like hybrids. This method stabilizes the delicate human cell membranes, introducing the potential for the study of human cell membranes and of their constituents in vitro in a more robust environment., Cell-like hybrids from natural and synthetic amphiphiles provide a platform to engineer functions of synthetic cells and protocells. Cell membranes and vesicles prepared from human cell membranes are relatively unstable in vitro and therefore are difficult to study. The thicknesses of biological membranes and vesicles self-assembled from amphiphilic Janus dendrimers, known as dendrimersomes, are comparable. This feature facilitated the coassembly of functional cell-like hybrid vesicles from giant dendrimersomes and bacterial membrane vesicles generated from the very stable bacterial Escherichia coli cell after enzymatic degradation of its outer membrane. Human cells are fragile and require only mild centrifugation to be dismantled and subsequently reconstituted into vesicles. Here we report the coassembly of human membrane vesicles with dendrimersomes. The resulting giant hybrid vesicles containing human cell membranes, their components, and Janus dendrimers are stable for at least 1 y. To demonstrate the utility of cell-like hybrid vesicles, hybrids from dendrimersomes and bacterial membrane vesicles containing YadA, a bacterial adhesin protein, were prepared. The latter cell-like hybrids were recognized by human cells, allowing for adhesion and entry of the hybrid bacterial vesicles into human cells in vitro.

General anesthetics inhibit voltage-gated sodium channels by unknown molecular mechanisms. Using computation-guided NMR and electrophysiology analyses, Wang et al. show that propofol binds to the prokaryotic sodium channel NaChBac at multiple distinct sites., Voltage-gated sodium (NaV) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic NaV channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects on NaChBac function and nearly identical anesthetizing effects on tadpole mobility. Using quantitative analysis by 19F-NMR saturation transfer difference spectroscopy, we reveal strong intermolecular cross-relaxation rate constants between 4-fluoropropofol and four different regions of NaChBac, including the activation gate and selectivity filter in the pore, the voltage sensing domain, and the S4–S5 linker. Unlike volatile anesthetics, 4-fluoropropofol does not bind to the extracellular interface of the pore domain. Collectively, our results show that propofol inhibits NaChBac at multiple sites, likely with distinct modes of action. This study provides a molecular basis for understanding the net inhibitory action of propofol on NaV channels.

Solid, liquid and alloyed phases of gallium play a role in a variety of important technological applications. While many of the gallium phases involved in these applications are metallic, some have...

The in vitro antidiabetic and antihyperlipidemic activities of an alcoholic extract of Trigonella stellata were evaluated in terms of the activation of PPARα and PPARγ in human hepatoma (HepG2) cells. The extract was investigated phytochemically, aiming at the isolation of the most active compounds to be used as a platform for drug discovery. Three new isoflavans, (3S,4R)-4,2′,4′-trihydroxy)-7-methoxyisoflavan (1), (3R,4S)-4,2′,4′-trihydroxy-7-methoxy-4′-O-β-d-glucopyranosylisoflavan (2), and (2S,3R,4R)-4,2′,4′-trihydroxy-2,7-dimethoxyisoflavan (3), were isolated and characterized along with the five known compounds p-hydroxybenzoic acid (4), 7,4′-dihydroxyflavone (5), dihydromelilotoside (6), quercetin-3,7-O-α-l-dirhamnoside (7), and soyasaponin I (8). The structures of 1–3 were elucidated using various spectroscopic techniques including HRESIMS and 1D and 2D NMR. The absolute stereochemistry of the new isoflavans (1–3) was determined using both experimental and calculated electronic circular dichroism a...

The conformational stability of synthesized diphenyloxalohydrazide and dibenzoyloxalohydrazide fluoro derivatives has been investigated by extensive NMR studies that are ascertained by various levels of theoretical calculations. Two-dimensional 1H–19F HOESY NMR experiments revealed the close spatial proximity between two NMR-active nuclei, confirming the hydrogen bond (HB)-mediated interaction between them, further aiding in establishing the probable stable conformations of these molecules. The relaxed potential energy scan disclosed the energy-minimized most stable structure among the several possible multiple conformations, which is in concurrence with NMR interpretations. Atomistic molecular dynamics simulations have been employed to unequivocally establish the conformational stability and the nature of HB formation at varied temperatures. With the possibility of occurrence of a number of probable conformations, the percentage of occurrences of different types of HBs in them was determined by MD simula...

Supramolecular orientational memory (SOM) provides a route to otherwise inaccessible nanoscale architectures for certain molecules. In these privileged cases, columnar domains organized from self-assembling dendrons undergo reorientation during heating to, and subsequent cooling from, a 3D phase composed of “spheres”, such as a body-centered cubic phase or a Pmn cubic phase, known also as Frank-Kasper A15. The directions of the reoriented columns preserve key interactions from the preceding cubic phase. However, SOM was observed so far in a very limited number of assemblies. The molecular determinants enabling SOM, and its generality, remain poorly understood. Here we report the synthesis and structural and retrostructural analysis of a perylene bisimide (PBI) with two self-assembling benzyl ether dendrons, 3,5-G2-PBI, and compare its assemblies with those of a previously reported PBI, 3,4,5-G2-PBI, which exhibits SOM and has an additional minidendritic building block in its dendrons. The removal of this minidendron in 3,5-G2-PBI eliminates its ability to self-assemble into supramolecular spheres and organize into a cubic phase, thereby precluding 3,5-G2-PBI from exhibiting SOM. This finding demonstrates hierarchical transfer of structural information from primary structure to material function, analogous to the misfolding of proteins into toxic structures such as those implicated in Alzheimer's and Prion diseases. The concepts exemplified here provide new insights into the hierarchical basis for SOM and will aid in the translation of the SOM concept to a broader diversity of soft matter such as block copolymers and surfactants.

Photooxygenation of Δ8 tetrahydrocannabinol (Δ8-THC), Δ9 tetrahydrocannabinol (Δ9-THC), Δ9 tetrahydrocannabinolic acid (Δ9-THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides. Testing these compounds for their modulatory effect on cannabinoid receptors CB1 and CB2 led to the identification of 7 and 21 as CB1 partial agonists with Ki values of 0.043 μM and 0.048 μM, respectively and 23 as a cannabinoid with high binding affinity for CB2 with Ki value of 0.0095 μM, but much less affinity towards CB1 (Ki 0.467 μM). The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC50 values ranging from 4.2 to 8.5 μg/mL. Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens.

Hexagonal borocarbonitrides (BCN) are a class of 2D materials, which display excellent catalytic activity for water splitting. Here, we report analysis of thermal stability, phonons and thermal conductivity of BCN monolayers over a wide range of temperatures using classical molecular dynamics simulations. Our results show that in contrast to the case of graphene and boron nitride monolayers, the out-of-plane phonons in BCN monolayers induce an asymmetry in the phonon density of states at all temperatures. Despite possessing lower thermal conducting properties compared to graphene and BN monolayers, the BCN nanosheets do not lose thermal conductivity as much as graphene and BN in the studied temperature range of 200-1000 K, and thus, the BCN nanosheets are suitable for thermal interface device applications over a wide range of temperatures. Besides their promising role in water splitting, the above results highlight the possibility of expanding the use of BCN 2D materials in thermal management applications and thermoelectrics., Comment: 6 pages, 4 figures

We show that intercalation of cations (Na+, Ca2+, Ni2+, and Co2+) into the interlayer region of 1T-MoS2 is an effective strategy to lower the overpotential for the hydrogen evolution reaction (HER). In acidic media the onset potential for 1T-MoS2 with intercalated ions is lowered by ∼60 mV relative to that for pristine 1T-MoS2 (onset of ∼180 mV). Density functional theory (DFT) calculations show a lowering in the Gibbs free energy for H-adsorption (ΔGH) on these intercalated structures relative to intercalant-free 1T-MoS2. The DFT calculations suggest that Na+ intercalation results in a ΔGH close to zero. Consistent with calculation, experiments show that the intercalation of Na+ ions into the interlayer region of 1T-MoS2 results in the lowest overpotential for the HER.

The confined environment presented by layered transition metal oxides is conducive to a variety of chemical reactions. Despite intense interest in these materials, little is known regarding the microscopic details relevant to their catalytic activity. We characterize aspects of the dynamics governing a redox reaction in the interlayer environment between manganese dioxide sheets. The nonequilibrium solvation dynamics surrounding charge transfer between an ion and the surface are highly non-linear and exhibit long-time relaxation that is governed by collective dynamics. These dynamics are rationalized in terms of structural rearrangements, allowing connections to be made to more complex reactions in these materials.

Zika virus (ZIKV) infection is associated with microcephaly in neonates and Guillain-Barre syndrome in adults. ZIKV produces a class of nonstructural (NS) regulatory proteins that play a critical role in viral transcription and replication, including NS5, which possesses RNA-dependent RNA polymerase (RdRp) activity. Here we demonstrate that rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infection, inhibits the enzymatic activity of NS5 and suppresses ZIKV infection and replication in primary human astrocytes. Similarly, other members of the NNRTI family, including etravirine and efavirenz, showed inhibitory effects on viral infection of brain cells. Site-directed mutagenesis identified 14 amino acid residues within the NS5 RdRp domain (AA265-903), which are important for the RPV interaction and the inhibition of NS5 polymerase activity. Administration of RPV to ZIKV-infected interferon-alpha/beta receptor (IFN-A/R) knockout mice improved the clinical outcome and prevented ZIKV-induced mortality. Histopathological examination of the brains from infected animals revealed that RPV reduced ZIKV RNA levels in the hippocampus, frontal cortex, thalamus, and cerebellum. Repurposing of NNRTIs, such as RPV, for the inhibition of ZIKV replication offers a possible therapeutic strategy for the prevention and treatment of ZIKV-associated disease.

The Shinoda-DeVane-Klein (SDK) model is herein demonstrated to be a viable coarse-grain model for performing molecular simulations of polyethylene (PE), affording new opportunities to advance molecular-level, scientific understanding of PE materials and processes. Both structural and dynamical properties of entangled PE melts are captured by the SDK model, which also recovers important aspects of PE crystallization phenomenology. Importantly, the SDK model can be used to represent a variety of materials beyond PE and has a simple functional form, making it unique among coarse-grain PE models. This study expands the suite of tools for studying PE in silico and paves the way for future work probing PE and PE-based composites at the molecular level.

6 p.-5 fig.-2 tab., Glycan-lectin recognition is assumed to elicit its broad range of (patho)physiological functions via a combination of specific contact formation with generation of complexes of distinct signal-triggering topology on biomembranes. Faced with the challenge to understand why evolution has led to three particular modes of modular architecture for adhesion/growth-regulatory galectins in vertebrates, here we introduce protein engineering to enable design switches. The impact of changes is measured in assays on cell growth and on bridging fully synthetic nanovesicles (glycodendrimersomes) with a chemically programmable surface. Using the example of homodimeric galectin-1 and monomeric galectin-3, the mutual design conversion caused qualitative differences, i.e., from bridging effector to antagonist/from antagonist to growth inhibitor and vice versa. In addition to attaining proof-of-principle evidence for the hypothesis that chimera-type galectin-3 design makes functional antagonism possible, we underscore the value of versatile surface programming with a derivative of the pan-galectin ligand lactose. Aggregation assays with N,N′-diacetyllactosamine establishing a parasite-like surface signature revealed marked selectivity among the family of galectins and bridging potency of homodimers. These findings provide fundamental insights into design-functionality relationships of galectins. Moreover, our strategy generates the tools to identify biofunctional lattice formation on biomembranes and galectin-reagents with therapeutic potential. © 2019 National Academy of Sciences., Financial support from NSF Grants DMR-1066116, DMR-1720530, and DMR-1807127 (to V.P.), the P. Roy Vagelos Chair at the University of Pennsylvania (V.P.), the Alexander von Humboldt Foundation(V.P.), NSF Grant DMR-1120901 (toM.L.K. and V.P.), NIH National Cancer Institute Grant R21-CA178754 (to M.C.), a China Scholarship Council PhD scholarship (to H.M.), Science Foundation Ireland Grant 13/IA/1959 (S.O.), and Spanish Grant BFU2016-77835R (to A.R.) is gratefully acknowledged.

Few polymers are as well-known as PPTA, the main constituent of Kevlar\textregistered{} fibers. To achieve high mechanical strength, PPTA chains must be treated with sulfuric acid, which is removed after fibers are formed. However, simulations show that tiny clusters of sulfuric acid remain embedded deeply within the fibers. Their presence is likely to go undetected, but can severely affect the material's strength under the high-strain conditions of its intended use. If the process behind the strength of PPTA fibers is also directly responsible for their main weakness, a solvent-free process is a promising route toward stronger materials

Significance The seminal fluid mosaic model of the cell membranes suggests a lipid bilayer sea, in which cholesterol, proteins, glycoconjugates, and other components are swimming. Complementing this view, a microsegregated rafts model predicts clusters of components that function as relay stations for intracellular signaling and trafficking. However, elucidating the arrangement of glycoconjugates responsible for communication and recognition between cells, and cells with proteins remains a challenge. Herein, designed dendritic macromolecules are shown to self-assemble into vesicles that function as biological-membrane mimics with controlled density of sugar moieties on their periphery. Surprisingly, lowering sugar density elicits higher bioactivity to sugar-binding proteins. This finding informs a design principle for active complex soft matter with potential for applications in cellular biology and nanomedicine., Self-assembling dendrimers have facilitated the discovery of periodic and quasiperiodic arrays of supramolecular architectures and the diverse functions derived from them. Examples are liquid quasicrystals and their approximants plus helical columns and spheres, including some that disregard chirality. The same periodic and quasiperiodic arrays were subsequently found in block copolymers, surfactants, lipids, glycolipids, and other complex molecules. Here we report the discovery of lamellar and hexagonal periodic arrays on the surface of vesicles generated from sequence-defined bicomponent monodisperse oligomers containing lipid and glycolipid mimics. These vesicles, known as glycodendrimersomes, act as cell-membrane mimics with hierarchical morphologies resembling bicomponent rafts. These nanosegregated morphologies diminish sugar–sugar interactions enabling stronger binding to sugar-binding proteins than densely packed arrangements of sugars. Importantly, this provides a mechanism to encode the reactivity of sugars via their interaction with sugar-binding proteins. The observed sugar phase-separated hierarchical arrays with lamellar and hexagonal morphologies that encode biological recognition are among the most complex architectures yet discovered in soft matter. The enhanced reactivity of the sugar displays likely has applications in material science and nanomedicine, with potential to evolve into related technologies.

We demonstrate that nascent polymer crystals (i.e., nuclei) are anisotropic entities, with neither spherical nor cylindrical geometry, in contrast to previous assumptions. In fact, cylindrical, spherical, and other high symmetry geometries are thermodynamically unfavorable. Moreover, post-critical transitions are necessary to achieve the lamellae that ultimately arise during the crystallization of semicrystalline polymers. We also highlight how inaccurate treatments of polymer nucleation can lead to substantial errors (e.g., orders of magnitude discrepancies in predicted nucleation rates). These insights are based on quantitative analysis of over four million crystal clusters from the crystallization of prototypical entangled polyethylene melts. New comprehensive bottom-up models are needed to capture polymer nucleation., Comment: 19 pages long with 5 figures

1st Symposium on Rational Design of Multifunctional Renewable-Resourced Materials, Boston, MA, USA, 19 Aug 2018 - 23 Aug 2018; Biomacromolecules 20(2), 712-727 (2019). doi:10.1021/acs.biomac.8b01405 special issue: "Special issue: The Rational Design of Multifunctional Renewable-Resourced Materials", Published by American Chemical Soc., Columbus, Ohio

Nonlamellar lipid arrangements, including cubosomes, appear in unhealthy cells, e.g., when they are subject to stress, starvation, or viral infection. The bioactivity of cubosomes—nanoscale particles exhibiting bicontinuous cubic structures—versus more common vesicles is an unexplored area due to lack of suitable model systems. Here, glycodendrimercubosomes (GDCs)—sugar-presenting cubosomes assembled from Janus glycodendrimers by simple injection into buffer—are proposed as mimics of biological cubic membranes. The bicontinuous cubic GDC architecture has been demonstrated by electron tomography. The stability of these GDCs in buffer enabled studies on lectin-dependent agglutination, revealing significant differences compared with the vesicular glycodendrimersome (GDS) counterpart. In particular, GDCs showed an increased activity toward concanavalin A, as well as an increased sensitivity and selectivity toward two variants of banana lectins, a wild-type and a genetically modified variant, which is not exhibited by GDSs. These results suggest that cells may adapt under unhealthy conditions by undergoing a transformation from lamellar to cubic membranes as a method of defense., A sugar-presenting cubosome is proposed as a biomimetic model for cubic membranes found in some diseased cells and provides, via agglutination with sugar receptors, clues to the biological rationale for the transition from lamellar to cubic membranes.

The modular synthesis of a library containing seven self-assembling amphiphilic Janus dendrimers is reported. Three of these molecules contain environmentally friendly chiral-racemic fluorinated dendrons in their hydrophobic part (RF), one contains achiral hydrogenated dendrons (RH), while one denoted hybrid Janus dendrimer, contains a combination of chiral-racemic fluorinated and achiral hydrogenated dendrons (RHF) in its hydrophobic part. Two Janus dendrimers contain either chiral-racemic fluorinated dendrons and a green fluorescent dye conjugated to its hydrophilic part (RF-NBD) or achiral hydrogenated and a red fluorescent dye in its hydrophilic part (RH-RhB). These RF, RH, and RHF Janus dendrimers self-assembled into unilamellar or onion-like soft vesicular dendrimersomes (DSs), with similar thicknesses to biological membranes by simple injection from ethanol solution into water or buffer. Since RF and RH dendrons are not miscible, RF-NBD and RH-RhB were employed to investigate by fluorescence microscopy the self-sorting and co-assembly of RF and RH as well as of phospholipids into hybrid DSs mediated by the hybrid hydrogenated-fluorinated RHF Janus dendrimer. The hybrid RHF Janus dendrimer co-assembled with both RF and RH. Three-component hybrid DSs containing RH, RF, and RHF were formed when the proportion of RHF was higher than 40%. With low concentration of RHF and in its absence, RH and RF self-sorted into individual RH or RF DSs. Phospholipids were also co-assembled with hybrid RHF Janus dendrimers. The simple synthesis and self-assembly of DSs and hybrid DSs, their similar thickness with biological membranes and their imaging by fluorescence and 19F-MRI make them important tools for synthetic biology.

TRPV1 channels comprise four subunits containing six transmembrane segments (S1–S6) that surround a central pore. Kasimova et al. hypothesize that channel opening involves rotation of an S6 asparagine residue toward the pore, as well as associated pore hydration and external cavity dehydration., The transient receptor potential channel vanilloid type 1 (TRPV1) is activated by a variety of endogenous and exogenous stimuli and is involved in nociception and body temperature regulation. Although the structure of TRPV1 has been experimentally determined in both the closed and open states, very little is known about its activation mechanism. In particular, the conformational changes that occur in the pore domain and result in ionic conduction have not yet been identified. Here we suggest a hypothetical molecular mechanism for TRPV1 activation, which involves rotation of a conserved asparagine in S6 from a position facing the S4–S5 linker toward the pore. This rotation is associated with hydration of the pore and dehydration of the four peripheral cavities located between each S6 and S4–S5 linker. In light of our hypothesis, we perform bioinformatics analyses of TRP and other evolutionary related ion channels, evaluate newly available structures, and reexamine previously reported water accessibility and mutagenesis experiments. These analyses provide several independent lines of evidence to support our hypothesis. Finally, we show that our proposed molecular mechanism is compatible with the prevailing theory that the selectivity filter acts as a secondary gate in TRPV1.

Ultrahigh-molecular-weight polyethylene (UHMWPE) is of great interest as a next-generation body armor material because of its superior mechanical properties. However, such unique properties depend critically on its microscopic structure characteristics, including the degree of crystallinity, chain alignment, and morphology. Here, we present a highly aligned UHMWPE and its composite sheets containing uniformly dispersed boron nitride (BN) nanosheets. The dispersion of BN nanosheets into the UHMWPE matrix increases its mechanical properties over a broad temperature range. Experiments and simulation confirm that the alignment of chain segments in the composite matrix increases with temperature, leading to an improvement in mechanical properties at high temperature. Together with the large thermal conductivity of UHMWPE and BN, our findings serve to expand the application spectrum of highly aligned polymer nanocomposite materials for ballistic panels and body armor over a broad range of temperatures.

Although the structure of TRPV1 has been experimentally determined in both the closed and open states, very little is known about its activation mechanism. In particular, the conformational changes occurring in the pore domain and resulting in ionic conduction have not been identified yet. Here, we suggest a hypothetical molecular mechanism for TRPV1 activation, which involves the rotation of a conserved asparagine in S6 from the S4-S5 linker toward the pore. This rotation is correlated with the dehydration of four peripheral cavities located between S6 and the S4-S5 linker and the hydration of the pore. In light of our hypothesis, we perform bioinformatics analyses of TRP and other evolutionary related ion channels, analyze newly available structures and re-examine previously reported water accessibility and mutagenesis experiments. Overall, we provide several independent lines of evidence that corroborate our hypothesis. Finally, we show that the proposed molecular mechanism is compatible with the currently existing idea that in TRPV1 the selectivity filter acts as a secondary gate.

Significance Cells are decorated with charged and uncharged carbohydrate ligands known as glycans, which are responsible for several key functions, including their interactions with proteins known as lectins. Here, a platform consisting of synthetic nanoscale vesicles, known as glycodendrimersomes, which can be programmed with cell surface-like structural and topological complexity, is employed to dissect design aspects of glycan presentation, with specificity for lectin-mediated bridging. Aggregation assays reveal the extent of cross-linking of these biomimetic nanoscale vesicles—presenting both anionic and neutral ligands in a bioactive manner—with disease-related human and other galectins, thus offering the possibility of unraveling the nature of these fundamental interactions., Precise translation of glycan-encoded information into cellular activity depends critically on highly specific functional pairing between glycans and their human lectin counter receptors. Sulfoglycolipids, such as sulfatides, are important glycolipid components of the biological membranes found in the nervous and immune systems. The optimal molecular and spatial design aspects of sulfated and nonsulfated glycans with high specificity for lectin-mediated bridging are unknown. To elucidate how different molecular and spatial aspects combine to ensure the high specificity of lectin-mediated bridging, a bottom-up toolbox is devised. To this end, negatively surface-charged glycodendrimersomes (GDSs), of different nanoscale dimensions, containing sulfo-lactose groups are self-assembled in buffer from a synthetic sulfatide mimic: Janus glycodendrimer (JGD) containing a 3′-O-sulfo-lactose headgroup. Also prepared for comparative analysis are GDSs with nonsulfated lactose, a common epitope of human membranes. These self-assembled GDSs are employed in aggregation assays with 15 galectins, comprising disease-related human galectins, and other natural and engineered variants from four families, having homodimeric, heterodimeric, and chimera architectures. There are pronounced differences in aggregation capacity between human homodimeric and heterodimeric galectins, and also with respect to their responsiveness to the charge of carbohydrate-derived ligand. Assays reveal strong differential impact of ligand surface charge and density, as well as lectin concentration and structure, on the extent of surface cross-linking. These findings demonstrate how synthetic JGD-headgroup tailoring teamed with protein engineering and network assays can help explain how molecular matchmaking operates in the cellular context of glycan and lectin complexity.

Polar surfaces can interact strongly with nearby water molecules, leading to the formation of highly ordered interfacial hydration structures. This ordering can lead to frustration in the hydrogen bond network, and, in the presence of solutes, frustrated hydration structures. We study frustration in the hydration of cations when confined between sheets of the water oxidation catalyst manganese dioxide. Frustrated hydration structures are shown to have profound effects on ion-surface electron transfer through the enhancement of energy gap fluctuations beyond those expected from Marcus theory. These fluctuations are accompanied by a concomitant increase in the electron transfer rate in Marcus's normal regime. We demonstrate the generality of this phenomenon-enhancement of energy gap fluctuations due to frustration-by introducing a charge frustrated XY model, likening the hydration structure of confined cations to topological defects. Our findings shed light on recent experiments suggesting that water oxidation rates depend on the cation charge and Mn-oxidation state in these layered transition metal oxide materials.

A library of eight amphiphilic Janus glycodendrimers (Janus-GDs) presenting D-lactose (Lac) and a combination of Lac with up to eight methoxytriethoxy (3EO) units in a sequence-defined arrangement was synthesized via an iterative modular methodology. The length of the linker between Lac and the hydrophobic part of the Janus-GDs was also varied. Self-assembly by injection from THF solution into phosphate-buffered saline led to unilamellar, monodisperse glycodendrimersomes (GDSs) with dimensions predicted by Janus-GD concentration. These GDSs provided a toolbox to measure bioactivity profiles in agglutination assays with sugar-binding proteins (lectins). Three naturally occurring forms of the human adhesion/growth-regulatory lectin galectin-8, Gal-8S and Gal-8L, which differ by the length of linker connecting their two active domains, and a single amino acid mutant (F19Y), were used as probes to study activity and sensor capacity. Unpredictably, the sequence of Lac on the Janus-GDs was demonstrated to determine bioactivity, with the highest level revealed for a Janus-GD with six 3EO groups and one Lac. A further increase in Lac density was invariably accompanied by a substantial decrease in agglutination, whereas a decrease in Lac density resulted in similar or lower bioactivity and sensor capacity. Both changes in topology of Lac presentation of the GDSs and seemingly subtle alterations in protein structure resulted in different levels of bioactivity, demonstrating the presence of regulation on both GDS surface and lectin. These results illustrate the applicability of Janus-GDs to dissect structure-activity relationships between programmable cell surface models and human lectins in a highly sensitive and physiologically relevant manner.