Structural Motifs Research Articles

PSSKB: A Web Application to Study Protein Structures.

The proteins expressed during the cell cycle determine cell function and ensure signaling pathway activation in response to environmental influences. Developments in structural biology, biophysics, and bioinformatics provide information on the structure and function of particular proteins including that on the structural changes in proteins due to post-translational modification (PTM) and amino acid substitutions (AAS), which is essential for understanding protein function and life cycle. These are PTMs and AASs that often modulate the function and alter the stability and localization of a protein in a cell. PSSKB is a platform that integrates all necessary tools for modeling the five common natural modifications and all canonical AASs in proteins. The available tools are not limited to the local database, so the user can select a protein from Uniprot ID or PDB ID. The result will be a three-dimensional (3D) representation of the modified structure, as well as an analysis of the changes in the performance of the intact and modified structures after energy minimization compared with the original structure, which not only makes it possible to evaluate AAS/PTM influence of on a protein's characteristics but also to use the 3D model for further studies. Additionally, PSSKB enables the user to search, align, overlay, and determine the exact coordinates of protein structure fragments. The search results are a set of structural motifs similar to the query and ranked by statistical significance. The platform is fully functional and publicly available at https://psskb.org/. No registration is required to access the platform. A tutorial video can be found at https://psskb.org/page/about. Services provided on the platform are based on previously developed and published software. SCPacker applied for PTM Modeling and AAS services available at GitHub (https://github.com/protdb/SCPacker). SaFoldNet applied for a Similar Search service is also available at GitHub (https://github.com/protdb/ABBNet).

Slowly quenched, high pressure glassy B2O3 at DFT accuracy.

Modeling inorganic glasses requires an accurate representation of interatomic interactions, large system sizes to allow for intermediate-range structural order, and slow quenching rates to eliminate kinetically trapped structural motifs. Neither first principles-based nor force field-based molecular dynamics (MD) simulations satisfy these three criteria unequivocally. Herein, we report the development of a machine learning potential (MLP) for a classic glass, B2O3, which meets these goals well. The MLP is trained on condensed phase configurations whose energies and forces on the atoms are obtained using periodic quantum density functional theory. Deep potential MD simulations based on this MLP accurately predict the equation of state and the densification of the glass with slower quenching from the melt. At ambient conditions, quenching rates larger than 1011 K/s are shown to lead to artifacts in the structure. Pressure-dependent x-ray and neutron structure factors from the simulations compare excellently with experimental data. High-pressure simulations of the glass show varied coordination geometries of boron and oxygen, which concur with experimental observations.

An Automated Approach for Domain-Specific Knowledge Graph Generation─Graph Measures and Characterization.

In 2020, nearly 3 million scientific and engineering papers were published worldwide (White, K. Publications Output: U.S. Trends And International Comparisons). The vastness of the literature that already exists, the increasing rate of appearance of new publications, and the timely translation of artificial intelligence methods into scientific and engineering communities have ushered in the development of automated methods for mining and extracting information from technical documents. However, domain-specific approaches for extracting knowledge graph representations from semantic information remain limited. In this paper, we develop a natural language processing (NLP) approach to extract knowledge graphs resulting in a semantically structured network (SSN) that can be queried. After a detailed exposition of the modeling method, the approach is demonstrated specifically for the synthetic chemistry of organic molecules from the text of approximately 100,000 full-length patents. In this paper, we focus specifically on characterizing the knowledge graph to develop insights into the linguistic patterns and trends within the data and to establish objective graph characteristics that may enable comparisons among other text-based knowledge graphs across domains. Graph characterization is performed for network motif structures, assortativity, and eigenvector centrality. The structural information provided by the measures reveals language tendencies commonly employed by authors in the text discourse for chemical reactions. These include observations of the prevalence of descriptions of specific compound names, that common solvents and drying agents cut across large numbers of chemical synthesis approaches, and that power-law trends clearly emerge in the limit of larger corpora. The findings provide important quantitative characterizations of knowledge graphs for use in validation in large data settings.

Where Does the Proton Go? Structure and Dynamics of Hydrogen-Bond Switching in Aminophosphine Chalcogenides.

Aminophosphates are the focus of research on prebiotic phosphorylation chemistry. Their bifunctional nature also makes them a powerful class of organocatalysts. However, the structural chemistry and dynamics of proton-binding in phosphorylation and organocatalytic mechanisms are still not fully understood. Aminophosphine chalcogenides, preserving the H2N-P+-Ch- structural motif, represent well-suited molecular models that mimic proton-binding, hydrogen-bond switching and supramolecular self-assembling behavior of catalytically and prebiotically relevant molecules. Through spectroscopic (IR, 1H DOSY, 15N NMR), molecular dynamics, and computational investigations, the dynamic proton switching capability of aminophosphate analogs was demonstrated. It was shown under which conditions the amino (NH2) or chalcogen (Ch) functions in H2N-P+-Ch- structural units are protonated. In fact, all conceivable modes of hydrogen-bonding were identified, revealing substantial differences between the oxygen derivative and the heavier congeners. Using coordinating anions, supramolecular zigzag- and cube-shaped arrangements were found in the solid-state and in solution. After break-up of the cube structure, the sulfides and selenides no longer form stable interactions with HCl molecules. In the absence of coordinating anions, protonation of the chalcogen function is preferred. In contrast to the oxygen derivative, the heavier congeners show dynamic intramolecular proton-hopping between the chalcogen and the amino function.

Where Does the Proton Go? Structure and Dynamics of Hydrogen‐Bond Switching in Aminophosphine Chalcogenides

Aminophosphates are the focus of research on prebiotic phosphorylation chemistry. Their bifunctional nature also makes them a powerful class of organocatalysts. However, the structural chemistry and dynamics of proton‐binding in phosphorylation and organocatalytic mechanisms are still not fully understood. Aminophosphine chalcogenides, preserving the H2N–P+–Ch− structural motif, represent well‐suited molecular models that mimic proton‐binding, hydrogen‐bond switching and supramolecular self‐assembling behavior of catalytically and prebiotically relevant molecules. Through spectroscopic (IR, 1H DOSY, 15N NMR), molecular dynamics, and computational investigations, the dynamic proton switching capability of aminophosphate analogs was demonstrated. It was shown under which conditions the amino (NH2) or chalcogen (Ch) functions in H2N–P+–Ch− structural units are protonated. In fact, all conceivable modes of hydrogen‐bonding were identified, revealing substantial differences between the oxygen derivative and the heavier congeners. Using coordinating anions, supramolecular zigzag‐ and cube‐shaped arrangements were found in the solid‐state and in solution. After break‐up of the cube structure, the sulfides and selenides no longer form stable interactions with HCl molecules. In the absence of coordinating anions, protonation of the chalcogen function is preferred. In contrast to the oxygen derivative, the heavier congeners show dynamic intramolecular proton‐hopping between the chalcogen and the amino function.

Sustainable Sulfur Conversionto Donor‐Acceptor Ladder Polymer Networks through Mechanochemical Nucleophilic Aromatic Substitution for Efficient CO2 Photoreduction

The development of synthetic methods capable of converting elemental sulfur into conjugated porous sulfur‐rich polymers remains a great challenge, although direct utilization of this readily available feedstock can significantly enrich its uses and circumvent environmental problems during sulfur storage. We report herein mechanochemical (MC) nucleophilic aromatic substitution (SNAr) that enables sustainable sulfur conversion into thianthrene‐bridged porous ladder polymer networks with dense donor‐acceptor (D‐A) molecular junctions. We demonstrate that the key lies in the generation of bent thianthrene units through a solid‐state ball‐milling condensation reaction between 1,2‐dihaloarenes and elemental sulfur. The assembling of D‐A structural motifs into porous networks affords efficient visible‐light‐driven photocatalytic reduction of carbon dioxide (CO2) with water (H2O) vapor, in the absence of any additional photosensitizer, sacrificial agents or cocatalysts. Exceptional photoinduced charge separation along with boosted exciton dissociation results in a high‐performance of carbon monoxide (CO) production rate of 306.1 μmol g–1 h–1 with near 100% CO selectivity, which is accompanied by H2O oxidation to O2, as confirmed by both experimental and theoretical results. We anticipate this novel MC SNAr approach will advance processing techniques for sustainable sulfur utilization and facilitate new possibilities for the synthesis of D‐A ladder polymer networks with promising potential in photocatalysis.

Identification of Fungal Metabolite Gliotoxin as a Potent Inhibitor Against Bacterial O-Acetylserine Sulfhydrylase CysK and CysM

Cysteine is an essential amino acid for sustaining life, including protein synthesis, and serves as a precursor for antioxidant glutathione. Pathogenic bacteria synthesize cysteine via a two-step enzymatic process using serine as the starting material. The first step is catalyzed by serine acetyltransferase, also known as CysE, and the second by O-acetylserine sulfhydrylase (OASS), referred to as CysK or CysM. This cysteine biosynthetic pathway in bacteria differs significantly from that in mammals, making it an attractive target for the development of novel antibacterial agents. In this study, we aimed to identify OASS inhibitors. To achieve this, a high-throughput screening system was developed to analyze compounds capable of inhibiting CysK/CysM activity. Screening 168,640 compounds from a chemical library revealed that gliotoxin, a fungal metabolite, strongly inhibits both CysK and CysM. Furthermore, gliotoxin significantly suppressed the growth of Salmonella enterica serovar Typhimurium, a Gram-negative bacterium, under cystine-deficient conditions. Gliotoxin possesses a unique disulfide structure classified as epipolythiodioxopiperazine. To date, no studies have reported OASS inhibition by compounds with this structural motif, highlighting its potential for future structural optimization. The screening system developed in this study is expected to accelerate the discovery of functional CysK/CysM inhibitors, providing a foundation for novel antibacterial strategies.

Emerging Physics in Magnetic Organic-Inorganic Hybrid Systems.

The hybrid magnetic heterostructures and superlattices, composed of organic and inorganic materials, have shown great potential for quantum computing and next-generation information technology. Organic materials generally possess designable structural motifs and versatile optical, electronic, and magnetic properties, but are too delicate for robust integration into solid-state devices. In contrast, inorganic systems provide robust solid-state interface and excellent electronic properties but with limited customization space. Combining these two systems and taking respective advantages to exploit exotic physical properties has been a promising research direction but with tremendous challenges. Herein, we review the material preparation methods and discuss the emerging physical properties discovered in such magnetic organic-inorganic hybrid systems (MOIHSs), including recent progress on designable magnetic property modification, exchange bias effect, and the interplay of ferromagnetism and superconductivity, which provide a promising material platform for emerging magnetic memory and spintronic device applications.

Electrochemical Cyclopropanation of Unactivated Alkenes with Methylene Compounds

Cyclopropanes are prevalent in natural products, pharmaceuticals, and bioactive compounds, functioning as a significant structural motif. Although a series of methods have been developed for the construction of the cyclopropane skeleton, the development of a direct and efficient strategy for the rapid synthesis of cyclopropanes from bench‐stable starting materials with a broad substrate scope and functional group tolerance remains challenging and highly desirable. Herein, we present an electrochemical method for the direct cyclopropanation of unactivated alkenes using active methylene compounds. The strategy shows a broad substrate scope with a high level of functional group compatibility, as well as potential application as demonstrated by late‐stage cyclopropanation of complex molecules and drug derivatives. Further mechanistic investigations suggest that Cp2Fe (Fc) plays an essential role as an oxidative mediator in generating radicals from active methylene compounds.

Electrochemical Cyclopropanation of Unactivated Alkenes with Methylene Compounds.

Cyclopropanes are prevalent in natural products, pharmaceuticals, and bioactive compounds, functioning as a significant structural motif. Although a series of methods have been developed for the construction of the cyclopropane skeleton, the development of a direct and efficient strategy for the rapid synthesis of cyclopropanes from bench-stable starting materials with a broad substrate scope and functional group tolerance remains challenging and highly desirable. Herein, we present an electrochemical method for the direct cyclopropanation of unactivated alkenes using active methylene compounds. The strategy shows a broad substrate scope with a high level of functional group compatibility, as well as potential application as demonstrated by late-stage cyclopropanation of complex molecules and drug derivatives. Further mechanistic investigations suggest that Cp2Fe (Fc) plays an essential role as an oxidative mediator in generating radicals from active methylene compounds.

A Comprehensive Review: Synthesis and Pharmacological Activities of 1,3,4-Oxadiazole Hybrid Scaffolds.

Heterocyclic derivatives, particularly those containing heteroatoms such as oxygen and nitrogen, represent a significant portion of currently marketed drugs. Among these, the aromatic heterocycle 1,3,4-oxadiazole, characterized by an N=C=O-linkage, stands out due to its remarkable biological activities. These activities include anti-inflammatory, anti-cancer, antioxidant, anti-tubercular, antiviral, anti-diabetic, and antibacterial effects. Notably, several commercially available medications, such as tiodazosin, raltegravir, zibotentan, and nesapidil, incorporate this structural motif. This review compiles and analyzes existing synthetic methods for preparing 1,3,4- oxadiazole and its derivatives. By examining various synthetic routes and methodologies, the review provides a detailed overview of the strategies employed to generate these biologically active compounds. The review highlights the potential of 1,3,4-oxadiazole derivatives in addressing the toxicity, side effects, and drug resistance commonly associated with existing anticancer therapies. By combining the 1,3,4-oxadiazole moiety with other heteroatoms, novel hybrid derivatives have been synthesized, demonstrating enhanced pharmacological activities across various therapeutic areas. This comprehensive review offers valuable insights into the synthesis and pharmacological applications of 1,3,4-oxadiazoles. It serves as a crucial resource for researchers exploring the development of new therapeutic compounds, with the ultimate goal of improving public health. The review builds on existing literature from the last two decades to present an exhaustive examination of the potential of 1,3,4-oxadiazole derivatives in drug development.

Identification of Benzothiophene-Derived Inhibitors of Flaviviruses by Targeting RNA-Dependent RNA Polymerase

Flaviviruses such as Dengue, West Nile, and Zika viruses are mosquito-borne RNA viruses that can cause serious diseases in humans. To develop effective drugs for treating these viruses’ infections, we create a new approach for developing common or shared drugs that may work for several different viral species of flaviviruses. It is based on the conserved RNA-dependent RNA polymerase (RdRp), which is the key enzyme for viral replication. We built up a common structure of RdRps (POLcon) from their consensus sequence. A conserved Triple-D structural motif was identified at the active site of POLcon that has been used for virtual compound screening. We have identified three inhibitors that have potent activities against Dengue, West Nile, and Zika viruses. All these three inhibitors are Benzothiophene derivatives. This is the first report of Benzothiophene-derived compounds as inhibitors for flaviviruses. Furthermore, our approach has provided a proof-of-concept that it is feasible to identify shared drugs for several different viral species of flaviviruses.

Unfolding of von Willebrand Factor Type D Like Domains Promotes Mucin Adhesion.

Mucins are the macromolecular key components of mucus. On wet epithelia of mammals, mucin solutions and gels act as powerful biolubricants and reduce friction and wear by generating a sacrificial layer and establishing hydration lubrication. Yet the structure-function relationship of mucin adhesion and lubrication remains elusive. We study the adhesion behavior of mucin using atomic force microscopy-based single molecule force spectroscopy with covalently attached, lab-purified salivary MUC5B and gastric MUC5AC. We can resolve the structural motifs mediating adhesion on chemically distinct substrates, such as highly oriented pyrolytic graphite and steel. We report on force-induced partial unfolding of the von Willebrand factor type D like domains and deliver their unfolding rates and free energy barriers. These domains serve to dissipate energy during the desorption process of mucins. Partial mucin unfolding might significantly contribute to the stability of a sacrificial mucin layer during shearing processes, enhancing the lubrication potential of mucin solutions.

Metal-directed hierarchical superhelices from hybrid peptide foldamers.

A superhelix is a three-dimensional arrangement of a helix in which the helix is coiled around a common axis. Here, we are reporting a short 12-helix of α,γ-hybrid peptides terminated by metal binding ligands, self-assembled into a right-handed superhelix around a common axis in the presence of Cd(II) ions. Furthermore, these superhelices are assembled into hierarchical superhelical β-sheet-type structural motifs in single crystals. The results reported here may give new insights to construct advanced self-assembled architectures from peptide foldamers.

Ab initio investigation of layered TMGeTe3 alloys for phase-change applications.

Chalcogenide phase-change materials (PCMs) are among the most mature candidates for next-generation memory technology. Recently, CrGeTe3 (CrGT) emerged as a promising PCM due to its enhanced amorphous stability and fast crystallization for embedded memory applications. The amorphous stability of CrGT was attributed to the complex layered structure of the crystalline motifs needed to initiate crystallization. A subsequent computational screening work identified several similar compounds with good thermal stability, such as InGeTe3, CrSiTe3 and BiSiTe3. Here, we explored the substitution of Cr in CrGT with other 3d metals and predicted four additional layered alloys to be dynamically stable, namely ScGeTe3, TiGeTe3, ZnGeTe3 and MnGeTe3. Thorough ab initio simulations performed on both crystalline and amorphous models of these materials indicate the former three alloys to be potential PCMs with sizable resistance contrast. Furthermore, we found that crystalline MnGeTe3 exhibits ferromagnetic behavior, whereas the amorphous state probably forms a spin glass phase. This makes MnGeTe3 a promising candidate for magnetic phase-change applications.

Allylic C–H oxygenation of unactivated internal olefins by the Cu/azodiformate catalyst system

Allylic ethers and alcohols are essential structural motifs commonly present in natural products and pharmaceuticals. Direct allylic C–H oxygenation of internal alkenes is one of the most direct methods, bypassing the necessity for an allylic leaving group that is needed in the traditional Tsuji–Trost reaction. Herein, we develop an efficient and practical method for synthesizing (E)-allyl ethers from readily available internal alkenes and alcohols or phenols via selective allylic C–H oxidation. Key advances include the use of a Cu/Azodiformate catalyst system to facilitate remote allylic C–H activation and the achievement of excellent chemoselectivity through a dynamic ligand exchange strategy using a bis(sulfonamide) ligand. This method features a broad substrate scope and functional group tolerance, successfully applied to the synthesis of various challenging medium-sized cyclic ethers (7-10 members) and large-ring lactones (14-20 members), with high regioselectivity and stereoselectivity.

Secondary Coordination Effects of Adjacent Metal Center in Metal-Nitrogen-Carbon Improve Scaling Relation of Oxygen Electrocatalysis.

Heterogenous single-atom catalysts (SACs) are reminiscent of homogeneous catalysts because of the similarity of structural motif of active sites, showing the potential of using the advantage of homogeneous catalysts to tackle challenges in hetereogenous catalysis. In heterogeneous oxygen electrocatalysis, the homogeneity of adsorption patterns of reaction intermediates leads to scaling relationships that limit their activities. In contrast, homogeneous catalysts can circumvent such limits by selectively altering the adsorption of intermediates through secondary coordination effects (SCEs). This inspired us to explore potential SCEs in metal-nitrogen-carbon (M-N-C), a promising type of oxygen evolution electrocatalyst. We introduced SCEs with a neighboring metal site that can modulate the adsorption strengths of oxygen-containing intermediates. First-principles calculations show that the second site in the heteronuclear duo four-nitrogen-coordinated metal center can induce SCEs that selectively stabilize the OOH intermediate but with minor effects on the OH intermediate and, thereby, disrupt the scaling relation between oxygen species and eventually increase the catalytic activity in oxygen evolution reactions. Additionally, the activity of oxygen reduction reaction of selected M-N-C is also enhanced by such SCE. Our computational work underscored the critical role SCEs can have in shaping activities of SACs, particularly in favorably altering scaling relationships, and demonstrated its potential to address catalytic challenges in heterogeneous catalysis.

New molecular hybrids integrated with quinoxaline and pyrazole structural motifs: VGFR2 inhibitors and apoptosis inducers.

The vascular endothelial growth factor receptor is essential for the angiogenesis of cancer. Tumor propagation was effectively suppressed by inhibiting VEGFR-2 activity. As a result, the target quinoxaline-pyrazole hybrids were created in a way that closely resembled the structural characteristics of VEGFR-2 inhibitors. The synthesized compounds were assessed in vitro using the MTT assay with doxorubicin serving as a reference standard for their cytotoxic properties against the HCT-116 and MCF-7 cell lines. Additionally, when tested on human normal fibroblasts (WI38), the promising cytotoxic compounds 8, 11, 13, and 15 were shown to be selective to cancer cells. Using ELISA, they showed mechanistically inhibitory activities against VEGFR-2; compound 13 was the most effective inhibitor, with an IC50 of 0.045±6.24 uM, surpassing sorafenib (IC50 of 0.049±5.24 μM). Notably, it was discovered that our target compound, 13, was 1.1 times more potent than sorafenib and 3.19 times more potent than sunitinib as a VGFRA2 inhibitor. Furthermore, Western blot analysis revealed that its VEGFR2 protein levels were noticeably higher than the control. Compound 13's selectivity towards VEGFR2 was further confirmed by testing it against other kinases, such as PDGFRA (IC50 0.329±0.014 μM) and EGFR (IC50 0.6±0.019 μM). Furthermore, 13 demonstrated a 50% decrease in VEGF-A secretion in comparison to the control group, demonstrating its anti-angiogenic quality. A scratch closure percentage of 57.78%, which was much lower than the 97.04 percent of untreated control cells, showed 13's anti-migratory capability. According to the cell cycle study, compound 13 induces apoptosis at the sub-G1 phase and terminates the cell cycle at the G1 phase. Consequently,flow cytometric analysis revealed that it caused apoptosis; compound 13 increases the BAX/Bcl-2 ratio from control to 13.66, and it also activates caspase 3 to 422.48±43.82 and induces p53 to 366.79±40.21. Docking simulations revealed potential binding modes and crucial structural elements of active drugs, and they were almost in agreement with enzymatic examination. For every hybrid, in silico physicochemical attributes, drug likeness metrics, and ligand efficiency were plausible. It's interesting to note that 13 and 15 are plausible medication candidates.

Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores.

Diastereodivergent synthesis of octahydrophenanthridinone and octahydrophenanthridine skeletons, structural motifs often found in biologically active natural products, is described. We previously reported a total synthesis of a pancratistatin analog using novel octahydrophenanthridinone construction. In this study, we examined the generality of our method and its extension to octahydrophenanthridine formation. Conjugate addition of diarylcuprates to nitrosocyclohexenes, which were generated in situ from 2-chlorocyclohexanone oximes, provided 2-arylcyclohexanone oximes. Subsequent reduction of the oxime moiety gave cis- and trans-configured amines. Both amines were separately converted into the corresponding octahydrophenanthridinones and octahydrophenanthridines via hexahydrophenanthridine intermediates.

Inhibition of chondroitin sulphate-degrading enzyme Chondroitinase ABC by dextran sulphate.

Chondroitin sulphate (CS) is a sulphated glycosaminoglycan (GAG) polysaccharide found on proteoglycans (CSPGs) in extracellular and pericellular matrices. Chondroitinase ABC (CSase ABC) derived from Proteus vulgaris is an enzyme that has gained attention for the capacity to cleave chondroitin sulphate (CS) glycosaminoglycans (GAG) from various proteoglycans such as Aggrecan, Neurocan, Decorin etc. The substrate specificity of CSase ABC is well-known for targeting various structural motifs of CS chains and has gained popularity in the field of neuro-regeneration by selective degradation of CS GAG chains. Within this context, our investigation into the biochemistry of CSase ABC led us to a previously unreported inhibition of CSase ABC activity by Dextran Sulphate (DexS). To understand the inhibitory effects of DexS, we compared its inhibition of CSase ABC to that of other polysaccharides such as Heparan Sulphate, Heparin, Colominic Acid, Fucoidan, and Dextran. This analysis identified key structural factors such as monosaccharide composition and linkage, sulphation degree and overall charge as influencing CSase ABC inhibition. Remarkably, DexS emerged as a unique inhibitor of CSase ABC, with distinctive inhibitory effects that correlate with its chain length. DexS has been used to reliably induce ulcerative colitis in mice, effectively mimicking inflammatory bowel diseases in humans, and has been previously shown to inhibit both RNA polymerase and reverse transcriptase. Our investigation emphasizes the interplay between the properties of DexS and CSase ABC, providing significant insights into the utilization of polysaccharide-based inhibitors for modulating enzyme activity.