Single Atom Substitution Research Articles

Capturing the Effects of Single Atom Substitutions on the Inhibition Efficiency of Glycogen Synthase Kinase-3β Inhibitors via Markov State Modeling and Experiments.

Small modifications in the chemical structure of ligands are known to dramatically change their ability to inhibit the activity of a protein. Unraveling the mechanisms that govern these dramatic changes requires scrutinizing the dynamics of protein-ligand binding and unbinding at the atomic level. As an exemplary case, we have studied Glycogen Synthase Kinase-3β (GSK-3β), a multifunctional kinase that has been implicated in a host of pathological processes. As such, there is a keen interest in identifying ligands that inhibit GSK-3β activity. One family of compounds that are highly selective and potent inhibitors of GSK-3β is exemplified by a molecule termed COB-187. COB-187 consists of a five-member heterocyclic ring with a thione at C2, a pyridine substituted methyl at N3, and a hydroxyl and phenyl at C4. We have studied the inhibition of GSK-3β by COB-187-related ligands that differ in a single heavy atom from each other (either in the location of nitrogen in their pyridine ring, or with the pyridine ring replaced by a phenyl ring), or in the length of the alkyl group joining the pyridine and the N3. The inhibition experiments show a large range of half-maximal inhibitory concentration (IC50) values from 10 nM to 10 μM, implying that these ligands exhibit vastly different propensities to inhibit GSK-3β. To explain these differences, we perform Markov State Modeling (MSM) using fully atomistic simulations. Our MSM results are in excellent agreement with the experiments in that they accurately capture differences in the binding propensities of the ligands. The simulations show that the binding propensities are related to the ligands' ability to attain a compact conformation where their two aromatic rings are spatially close. We rationalize this result by sampling numerous binding and unbinding events via funnel metadynamics simulations, which show that indeed while approaching the bound state, the ligands prefer to be in their compact conformation. We find that the presence of nitrogen in the aromatic ring increases the probability of attaining the compact conformation. Protein-ligand binding is understood to be dictated by the energetics of interactions and entropic factors, like the release of bound water from the binding pockets. This work shows that changes in the conformational distribution of ligands due to atom-level modifications in the structure play an important role in protein-ligand binding.

Selective CO2 Photoreduction into CH4 Triggered by the Synergy between Oxygen Vacancy and Ru Substitution under Near-Infrared Light Irradiation.

Near-infrared (NIR) light powdered CO2 photoreduction reaction is generally restricted to the separation efficiency of photogenerated carriers and the supply of active hydrogen (*H). Herein, the study reports a retrofitting hydrogenated MoO3-x (H-MoO3-x) nanosheet photocatalysts with Ru single atom substitution (Ru@H-MoO3-x) fabricated by one-step solvothermal method. Experiments together with theoretical calculations demonstrate that the synergistic effect of Ru substitution and oxygen vacancy can not only inhibit the recombination of photogenerated carriers, but also facilitate the CO2 adsorption/activation as well as the supply of *H. Compared with H-MoO3-x, the Ru@H-MoO3-x exhibit more favorable formation of *CHO in the process of *CO conversion due to the fast *H generation on electron-rich Ru sites and transfer to *CO intermediates, leading to the preferential photoreduction of CO2 to CH4 with high selectivity. The optimized Ru@H-MoO3-x exhibits a superior CO2 photoreduction activity with CH4 evolution rate of 111.6 and 39.0µmol gcatalyst -1 under full spectrum and NIR light irradiation, respectively, which is 8.8 and 15.0 times much higher than that of H-MoO3-x. This work provides an in-depth understanding at the atomic level on the design of NIR responsive photocatalyst for achieving the goal of carbon neutrality.

Using single atom substitution strategy for constructing a novel Se-substituted hemicyanine dye with hydroxyl group as an ideal activatable photosensitizer dye scaffold

Photodynamic therapy (PDT) is an effective method to treat diseases, especially for tumor treatment, with remarkable characteristics including good therapeutic results and low drug resistance, which has attracted the attention of researchers. The performances of photosensitizer dye largely determine the tumor treatment results. However, most of the reported photosensitive dyes belong to the “always-on” photosensitive property, which cannot avoid the photodamage caused to normal tissues during tumor PDT. By contrast, activatable photosensitizers possess the desirable characteristic of controllable phototoxicity, ensuring tumor safety treatment. Until now, ideal photosensitizer dye scaffold is still lacking. Therefore, constructing a universal photosensitive dye scaffold is a vital issue to be solved urgently. In this work, inspired by the single atom substitution strategy, the oxygen atom in classical hemicyanine dye has been replaced by selenium (Se) atom to obtain a novel Se-substituted hemicyanine dye with hydroxy group, HCySe-OH, as a novel dye platform for constructing activatable photosensitizers. We found that HCySe-OH had high singlet oxygen (1O2) generation ability and longer absorption and emission in contrast to the classical O-substituted hemicyanine, endowing its better biomedical application. Additionally, HCySe-OH was successfully utilized to kill cancer cells and bacteria under 760 nm laser irradiation. More importantly, we believe that numerous smart activatable photosensitizers will be developed based on this platform, HCySe-OH.

Effect of two-fold single-atom substitutions (S, Se; C, N) in band gap engineered donor-acceptor conjugated microporous polymers on the efficient aerobic photooxidation of aryl sulfides.

Substitution of a single atom in a photoactive system is capable of vastly altering its optoelectronic properties leading to the generation of an efficient photocatalyst. In this study, we explore the impact of two-fold single-atom substitutions on the optoelectronic properties and photocatalytic performance of donor-acceptor type conjugated microporous polymers (D-A CMPs). For this, three isostructural triphenylamine (TPA)-based D-A CMPs were synthesized namely PTPA-BT, PTPA-BS, and PTPA-PS containing 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole and [1,2,5]selenadiazolo[3,4-c]pyridine as the acceptor moieties, respectively. Firstly, PTPA-BT and PTPA-BS were synthesized using the S to Se single-atom substitution strategy, followed by the synthesis of PTPA-PS employing a second C to N single-atom substitution. The effect of single-atom substitution demonstrated drastic changes in their band gap, conductivity, and charge carrier dynamics, which in turn impacted their photocatalytic activity, although the change in their porosity was not much pronounced. In terms of photocatalytic detoxification of sulfur mustards, the activities of D-A CMPs follow the trend: PTPA-BS > PTPA-PS > PTPA-BT. In comparison with PTPA-BT (containing C, S) and PTPA-PS (containing N, Se), PTPA-BS (containing C, Se) exhibits a higher photocatalytic activity towards the photooxidation of thioanisole with >99% conversion and ∼93% isolated yield under visible-light illumination, which is attributed to its lower interfacial charge transfer resistance, stronger photocurrent response, optimal band gap and higher activity to generate superoxide anion radicals. Therefore, the two-fold single-atom substitution strategy is crucial for optimizing D-A CMPs for the photocatalytic oxidation of aryl sulfides. This approach allows fine-tuning of the optoelectronic properties to enhance photocatalytic efficiency and performance.

Sulfur-tetrazine as highly efficient visible-light activatable photo-trigger for designing photoactivatable fluorescence biomolecules.

Light-activated fluorescence represents a potent tool for investigating subcellular structures and dynamics, offering enhanced control over the temporal and spatial aspects of the fluorescence signal. While alkyl-substituted tetrazine has previously been reported as a photo-trigger for various fluorophore scaffolds, its limited photochemical efficiency and high activation energy have constrained its widespread application at the biomolecular level. In this study, we demonstrate that a single sulfur atom substitution of tetrazine greatly enhances the photochemical properties of tetrazine conjugates and significantly improves their photocleavage efficiency. Notably, the resulting sulfur-tetrazine can be activated using a lower-energy light source, thus transforming it into a valuable visible-light photo-trigger. To introduce this photo-trigger into biological systems, we have developed a series of visible-light activatable small molecular dyes, along with a photoactivatable noncanonical amino acid containing sulfur-tetrazine. Using the Genetic Code Expansion technology, this novel amino acid is genetically incorporated into fluorescent protein molecules, serving as a phototrigger to create an innovative photoactivatable protein. These advancements in tetrazine-scaffold photo-trigger design open up new avenues for generating photoactivatable biomolecules, promising to greatly facilitate the exploration of biological functions and structures.

Influence of donor point modifications on the assembly of chalcogen-bonded organic frameworks.

Incremental, single-atom substitutions of Se-based chalcogen bond (Ch-bond) donors with stronger donating Te centers were implemented in two new triptycene tris(1,2,5-chalcogenadiazole) tectons. The appreciably more favorable Ch-bonding ability of the Te-based donors promotes assembly of low-density networks and more stable Ch-bonded organic frameworks (ChOFs).

First-principles study of the ferrielectric of X-doped KNbO3 (X = Na, Rb, and Cs)

Perovskite ferroelectrics has great value and many new structures have been synthesized experimentally by doping with new components. But there were few studies on single atom substitution in theory. This article investigates the ferroelectricity of KNbO3 when some of the K atoms are replaced with elements of the same main group. Structural, polarization and electronic of different type KNbO3 were calculated using first principles calculations. Analysis of relaxed structure and electron charge shows that the different atom substitution produces different distortion. The combined analysis leads to the conclusion that the ferroelectricity decreases with increasing radius of the homologous atoms. This provides an explanation for the experimental data from another perspective.

Magneto-Optical Properties of Noble Metal Nanostructures.

The magneto-optical signatures of colloidal noble metal nanostructures, spanning both discrete nanoclusters (<2 nm) and plasmonic nanoparticles (>2 nm), exhibit rich structure-property correlations, impacting applications including photonic integrated circuits, light modulation, applied spectroscopy, and more. For nanoclusters, electron doping and single-atom substitution modify both the intensity of the magneto-optical response and the degree of transient spin polarization. Nanoparticle size and morphology also modulate the magnitude and polarity of plasmon-mediated magneto-optical signals. This intimate interplay between nanostructure and magneto-optical properties becomes especially apparent in magnetic circular dichroism (MCD) and magnetic circular photoluminescence (MCPL) spectroscopic data. Whereas MCD spectroscopy informs on a metal nanostructure's steady-state extinction properties, its MCPL counterpart is sensitive to electronic spin and orbital angular momenta of transiently excited states. This review describes the size- and structure-dependent magneto-optical properties of nanoscale metals, emphasizing the increasingly important role of MCPL in understanding transient spin properties and dynamics.

DNA damage, cell cycle perturbation and cell death by naphthalene diimide derivative in gastric cancer cells

Stomach cancer causes the third-highest cancer-related deaths worldwide. Limited availability of anticancer measures with higher efficiency and low unwanted toxicities necessitates the development of better cancer chemotherapeutics. Naphthalene diimide (NDI) derivatives have gained significant attention owing to their excellent anticancer potential. We evaluated the anticancer properties of NDI derivatives, 1a and 2a in cancer cell lines and found that 1a showed higher efficacy as compared to 2a exhibiting a remarkable difference in activity upon single atom substitution of C with N. Particularly, NDI 1a showed potent inhibitory activity against gastric cancer cell line AGS with IC50 of 2.0 μM. NDI 1a induced remarkable morphological changes and reduced clonogenicity as well as the migratory ability of AGS cells. The reduction in AGS cell migration was mediated through inhibition of Tyr397 p-FAK dephosphorylation at focal adhesion points leading to enhanced attachment of cells at contact points. NDI 1a caused extensive DNA double-strand-breaks (DSBs) leading to activation of p53 and its transcriptional target p21. Reduced nuclear BRCA1 but enhanced nuclear p53BP1 foci formation upon 1a treatment suggests that DNA DSB repair is mediated through error-prone NHEJ which led to the accumulation of extensive DNA damage. Combinatorial effects mediated by interactions of 1a with double-stranded DNA through minor groove binding as well as induction of intracellular ROS exacerbated the loss of genomic integrity induced by 1a. NDI 1a mediated DNA damage-induced S phase arrest; however, cells experiencing extensive and irreparable DNA damage underwent mitochondrial apoptosis through downregulation of anti-apoptotic protein p21. Furthermore, proliferation inhibitory activity of 1a is also attributed to inhibition of β−catenin/c-Myc axis in AGS cells with constitutively active β−catenin pathway. In vivo toxicity analysis of 1a revealed minimal systemic toxicity suggesting that compound 1a is a safe and potential candidate for the development of gastric cancer chemotherapeutics.

Electron delocalization refining via single atom substitution in conjugated organic polymers for enhanced photocatalytic CO2 conversion: Get the big picture from small details

The atom refining strategy is used for the design of COP-X (X = S, N, O) as the efficient photocatalysts for CO2 conversion. Both photoelectrochemical experiments and computational explorations demonstrate that the electron delocalization and reaction barrier can be well regulated by single atom substitution of S, N and O in the 1,3,5-triethynylbenzene linked COPs. Based on the prominent electron donating capacity of S, the fast electron transfer and prolonged lifetime of photoinduced charge carriers endow COP-S with superior photocatalytic CO2 conversion efficiency and selectivity. The CO production rate reaches 196.4 μmol g-1h−1 without the presence of cocatalysts and sacrificial agents, which is 2.1-folds and 2.5-folds of COP-N and COP-O. In particular, the oxidization of H2O to O2 is also realized on bulk COP-S. Our explorations expand the COPs skeleton engineering toolbox and provide new guidance for the design of efficient catalysts for solar energy utilizations.

Chemoselective Transamidation of Thioamides by Transition-Metal-Free N-C(S) Transacylation.

Thioamides represent highly valuable isosteric in the strictest sense "single-atom substitution" analogues of amides that have found broad applications in chemistry and biology. A long-standing challenge is the direct transamidation of thioamides, a process which would convert one thioamide bond (R-C(S)-NR1 R2 ) into another (R-C(S)-NR3 N4 ). Herein, we report the first general method for the direct transamidation of thioamides by highly chemoselective N-C(S) transacylation. The method relies on site-selective N-tert-butoxycarbonyl activation of 2° and 1° thioamides, resulting in ground-state-destabilization of thioamides, thus enabling to rationally manipulate nucleophilic addition to the thioamide bond. This method showcases a remarkably broad scope including late-stage functionalization (>100 examples). We further present extensive DFT studies that provide insight into the chemoselectivity and provide guidelines for the development of transamidation methods of the thioamide bond.

Structural impact of thioamide incorporation into a β-hairpin.

The thioamide is a naturally-occurring single atom substitution of the canonical amide bond. The exchange of oxygen to sulfur alters the amide's physical and chemical characteristics, thereby expanding its functionality. Incorporation of thioamides in prevalent secondary structures has demonstrated that they can either have stabilizing, destabilizing, or neutral effects. We performed a systematic investigation of the structural impact of thioamide incorporation in a β-hairpin scaffold with nuclear magnetic resonance (NMR). Thioamides as hydrogen bond donors did not increase the foldedness of the more stable “YKL” variant of this scaffold. In the less stable “HPT” variant of the scaffold, the thioamide could be stabilizing as a hydrogen bond donor and destabilizing as a hydrogen bond acceptor, but the extent of the perturbation depended upon the position of incorporation. To better understand these effects we performed structural modelling of the macrocyclic folded HPT variants. Finally, we compare the thioamide effects that we observe to previous studies of both side-chain and backbone perturbations to this β-hairpin scaffold to provide context for our observations.

Xanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregates.

Proper three-dimensional structures are essential for maintaining the functionality of proteins and for avoiding pathological consequences of improper folding. Misfolding and aggregation of proteins have been both associated with neurodegenerative disease. Therefore, a variety of fluorogenic tools that respond to both polarity and viscosity have been developed to detect protein aggregation. However, the rational design of highly sensitive fluorophores that respond solely to polarity has remained elusive. In this work, we demonstrate that electron-withdrawing heteroatoms with (d-p)-π* conjugation can stabilize lowest unoccupied molecular orbital (LUMO) energy levels and promote bathochromic shifts. Guided by computational analyses, we have devised a novel series of xanthone-based solvatochromic fluorophores that have rarely been systematically studied. The resulting probes exhibit superior sensitivity to polarity but are insensitive to viscosity. As proof of concept, we have synthesized protein targeting probes for live-cell confocal imaging intended to quantify the polarity of misfolded and aggregated proteins. Interestingly, our results reveal several layers of protein aggregates in a way that we had not anticipated. First, microenvironments with reduced polarity were validated in the misfolding and aggregation of folded globular proteins. Second, granular aggregates of AgHalo displayed a less polar environment than aggregates formed by folded globular protein represented by Htt-polyQ. Third, our studies reveal that granular protein aggregates formed in response to different types of stressors exhibit significant polarity differences. These results show that the solvatochromic fluorophores solely responsive to polarity represent a new class of indicators that can be widely used for detecting protein aggregation in live cells, thus paving the way for elucidating cellular mechanisms of protein aggregation as well as therapeutic approaches to managing intracellular aggregates.

Single-Atom Engineering to Ignite 2D Transition Metal Dichalcogenide Based Catalysis: Fundamentals, Progress, and Beyond.

Single-atom catalysis has been recognized as a pivotal milestone in the development history of heterogeneous catalysis by virtue of its superior catalytic performance, ultrahigh atomic utilization, and well-defined structure. Beyond single-atom protrusions, two more motifs of single-atom substitutions and single-atom vacancies along with synergistic single-atom motif assemblies have been progressively developed to enrich the single-atom family. On the other hand, besides traditional carbon material based substrates, a wide variety of 2D transitional metal dichalcogenides (TMDs) have been emerging as a promising platform for single-atom catalysis owing to their diverse elemental compositions, variable crystal structures, flexible electronic structures, and intrinsic activities toward many catalytic reactions. Such substantial expansion of both single-atom motifs and substrates provides an enriched toolbox to further optimize the geometric and electronic structures for pushing the performance limit. Concomitantly, higher requirements have been put forward for synthetic and characterization techniques with related technical bottlenecks being continuously conquered. Furthermore, this burgeoning single-atom catalyst (SAC) system has triggered serial scientific issues about their changeable single atom-2D substrate interaction, ambiguous synergistic effects of various atomic assemblies, as well as dynamic structure-performance correlations, all of which necessitate further clarification and comprehensive summary. In this context, this Review aims to summarize and critically discuss the single-atom engineering development in the whole field of 2D TMD based catalysis covering their evolution history, synthetic methodologies, characterization techniques, catalytic applications, and dynamic structure-performance correlations. In situ characterization techniques are highlighted regarding their critical roles in real-time detection of SAC reconstruction and reaction pathway evolution, thus shedding light on lifetime dynamic structure-performance correlations which lay a solid theoretical foundation for the whole catalytic field, especially for SACs.

Desolvation of Peptide Bond by O to S Substitution Impacts Protein Stability

AbstractAmino acid side chains are key to fine‐tuning the microenvironment polarity in proteins composed of polar amide bonds. Here, we report that substituting an oxygen atom of the backbone amide bond with sulfur atom desolvates the thioamide bond, thereby increasing its lipophilicity. The impact of such local desolvation by O to S substitution in proteins was tested by synthesizing thioamidated variants of Pin1 WW domain. We observe that a thioamide acts in synergy with nonpolar amino acid side chains to reduce the microenvironment polarity and increase protein stability by more than 14 °C. Through favorable van der Waals and hydrogen bonding interactions, this single atom substitution significantly stabilizes proteins without altering the amino acid sequence and structure of the native protein.

Desolvation of Peptide Bond by O to S Substitution Impacts Protein Stability.

Amino acid side chains are key to fine-tuning the microenvironment polarity in proteins composed of polar amide bonds. Here, we report that substituting an oxygen atom of the backbone amide bond with sulfur atom desolvates the thioamide bond, thereby increasing its lipophilicity. The impact of such local desolvation by O to S substitution in proteins was tested by synthesizing thioamidated variants of Pin1 WW domain. We observe that a thioamide acts in synergy with nonpolar amino acid side chains to reduce the microenvironment polarity and increase protein stability by more than 14 °C. Through favorable van der Waals and hydrogen bonding interactions, this single atom substitution significantly stabilizes proteins without altering the amino acid sequence and structure of the native protein.

Investigation of p-type doping in β- and κ-Ga2O3

We have systematically investigated the effects of all possible combinations of vacancies and silicon substitutions on the electronic structure of the β and κ phases of Ga2O3 using plane-wave density functional theory (DFT) methods. It was found that VGa defects are associated with a sufficient shift of the Fermi level to lower energy to induce p-type behavior, with formation energies in the range of 9.0 ± 0.2 eV. Calculations with single atom substitutions in the κ phase, including nitrogen, phosphorous, and silicon, did not show p-type character, although NO substitutions may lead to shallow acceptor states. In the pursuit of elucidating how MOCVD growth of Ga2O3 can result in p-type behavior, as indicated by experimental results in the literature, we examined the role of combining hydrogen and silicon substitutions. The results showed that p-type behavior is observable when gallium atoms are substituted for hydrogen within the coordination sphere of SiO substitutions. This shows that silicon can act as an amphoteric dopant for p-type Ga2O3 semiconducting materials when hydrogen is included with formation energies<6.0 eV.

Effect of B and O doping on the electronic structure and quantum capacitance of carbon nitride monolayers using first-principles calculations

The structural, electronic, and capacitance properties of B- or O-doped carbon nitride monolayers were systematically investigated using first-principles calculations. Different single-atom substitutions (i.e., B or O dopant on a Cx or Ny substitution site) were considered for this work. The substitution site plays an important role in regulating the stability and electronic structure of carbon nitride monolayers. B or O doping could make carbon nitride monolayers produce large local density of states near Fermi level contributed mainly from the hybridization of the 2p states of C, N, and the doped atom (B or O), thus significantly improving conductivity, quantum capacitance, and surface charge density of the structures. The results show that the quantum capacitances of the B-doped carbon nitride monolayers are much greater than those of the B-doped graphene monolayers. Furthermore, B-doped C3N at the C1 site, B-doped tg-C3N4 at the N2 site, and O-doped tg-C3N4 at the N1 site are strongly recommended as the electrodes in symmetrical supercapacitors, while the other doped components could also be used as cathode or anode materials in asymmetrical supercapacitors. The findings of this study suggest that doped carbon nitride structures could be considered as promising electrode materials for supercapacitors.

Catalytically potent and selective clusterzymes for modulation of neuroinflammation through single-atom substitutions

Emerging artificial enzymes with reprogrammed and augmented catalytic activity and substrate selectivity have long been pursued with sustained efforts. The majority of current candidates have rather poor catalytic activity compared with natural molecules. To tackle this limitation, we design artificial enzymes based on a structurally well-defined Au25 cluster, namely clusterzymes, which are endowed with intrinsic high catalytic activity and selectivity driven by single-atom substitutions with modulated bond lengths. Au24Cu1 and Au24Cd1 clusterzymes exhibit 137 and 160 times higher antioxidant capacities than natural trolox, respectively. Meanwhile, the clusterzymes demonstrate preferential enzyme-mimicking catalytic activities, with Au25, Au24Cu1 and Au24Cd1 displaying compelling selectivity in glutathione peroxidase-like (GPx-like), catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) activities, respectively. Au24Cu1 decreases peroxide in injured brain via catalytic reactions, while Au24Cd1 preferentially uses superoxide and nitrogenous signal molecules as substrates, and significantly decreases inflammation factors, indicative of an important role in mitigating neuroinflammation.

Predicting human touch sensitivity to single atom substitutions in surface monolayers for molecular control in tactile interfaces.

The mechanical stimuli generated as a finger interrogates the physical and chemical features of an object form the basis of fine touch. Haptic devices, which are used to control touch, primarily focus on recreating physical features, but the chemical aspects of fine touch may be harnessed to create richer tactile interfaces and reveal fundamental aspects of tactile perception. To connect tactile perception with molecular structure, we systematically varied silane-derived monolayers deposited onto surfaces smoother than the limits of human perception. Through mechanical friction testing and cross-correlation analysis, we made predictions of which pairs of silanes might be distinguishable by humans. We predicted, and demonstrated, that humans can distinguish between two isosteric silanes which differ only by a single nitrogen-for-carbon substitution. The mechanism of tactile contrast originates from a difference in monolayer ordering, as quantified by the Hurst exponent, which was replicated in two alkylsilanes with a three-carbon difference in length. This approach may be generalizable to other materials and lead to new tactile sensations derived from materials chemistry.