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Motivated by the multiferroic effects and quantum magnetization plateaus in the skew chain antiferromagnets T 2 V 2 O 7 (T = Ni, Co), we have conducted a detailed density function theoretical study on Co 2 V 2 O 7. The results show that the nearest-neighbor interchain interaction (J 3 / k B = − 35.57 K) is not much greater than the intrachain interactions (J 1 / k B = − 19.54 K and J 2 / k B = 27.55 K), showing the absence of interchain dimerization of the Co ions. This indicates that the "dimer+monomer" model used for Ni 2 V 2 O 7 [Cao et al., Phys. Rev. B 106, 184409 (2022)] is no longer applicable to Co 2 V 2 O 7. Finally, the exact diagonalization of spin Hamiltonian, including anisotropic exchanges, produces the experimentally observed 1/2 and 3/4 magnetization plateaus. [ABSTRACT FROM AUTHOR]

Motivated by the multiferroic effects and quantum magnetization plateaus in the skew chain antiferromagnets T 2 V 2 O 7 (T = Ni, Co), we have conducted a detailed density function theoretical study on Co 2 V 2 O 7. The results show that the nearest-neighbor interchain interaction (J 3 / k B = − 35.57 K) is not much greater than the intrachain interactions (J 1 / k B = − 19.54 K and J 2 / k B = 27.55 K), showing the absence of interchain dimerization of the Co ions. This indicates that the "dimer+monomer" model used for Ni 2 V 2 O 7 [Cao et al., Phys. Rev. B 106, 184409 (2022)] is no longer applicable to Co 2 V 2 O 7. Finally, the exact diagonalization of spin Hamiltonian, including anisotropic exchanges, produces the experimentally observed 1/2 and 3/4 magnetization plateaus. [ABSTRACT FROM AUTHOR]

A proof-of-concept study is undertaken to demonstrate the utility of the machine learning combined with the thermodynamic perturbation theory (MLPT) to test the accuracy of electronic structure methods in finite-temperature thermodynamic calculations. As a test example, formic acid dimer is chosen, which is one of the systems included in the popular benchmark set S22 [Jurečka et al., Phys. Chem. Chem. Phys. 8, 1985–1993 (2006)]. Starting from the explicit molecular dynamics and thermodynamic integration performed at the PBE + D2 level, the MLPT is used to obtain fully anharmonic dimerization free and internal energies at the reference quality CCSD(T) level and 19 different density functional approximations, including GGA, meta-GGA, non-local, and hybrid functionals with and without dispersion corrections. Our finite-temperature results are shown to be both qualitatively and quantitatively different from those obtained using the conventional benchmarking strategy based on fixed structures. The hybrid functional HSE06 is identified as the best performing approximate method tested, with the errors in free and internal energies of dimerization being 36 and 41 meV, respectively. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations are conducted to systematically investigate the insertion of spherical nanoparticles (NPs) in polymer brushes as a function of their size, strength of their interaction with the polymers, polymer grafting density, and polymer chain length. For attractive interactions between the NPs and the polymers, the depth of NPs' penetration in the brush results from a competition between the enthalpic gain due to the favorable polymer–NP interaction and the effect of osmotic pressure resulting from displaced polymers by the NP's volume. A large number of simulations show that the average depth of the NPs increases by increasing the strength of the interaction strength. However, it decreases by increasing the NPs' diameter or increasing the polymer grafting density. While the NPs' effect on the polymer density is local, their effect on their conformations is long-ranged and extends laterally over length scales larger than the NP's size. This effect is manifested by the emergence of laterally damped oscillations in the normal component of the chains' radius of gyration. Interestingly, we found that for high enough interaction strength, two NPs dimerize in the polymer brush. The dimer is parallel to the substrate if the NPs' depth in the brush is shallow. However, the dimer is perpendicular to the substrate if the NPs' are deep in the brush. These results imply that polymer brushes can be used as a tool to localize and self-assemble NPs in polymer brushes. [ABSTRACT FROM AUTHOR]

Plants sense abscisic acid (ABA) using chemical-induced dimerization (CID) modules, including the receptor PYR1 and HAB1, a phosphatase inhibited by ligand-activated PYR1. This system is unique because of the relative ease with which ligand recognition can be reprogrammed. To expand the PYR1 system, we designed an orthogonal * module, which harbors a dimer interface salt bridge; X-ray crystallographic, biochemical and in vivo analyses confirm its orthogonality. We used this module to create PYR1*MANDI/HAB1* and PYR1*AZIN/HAB1*, which possess nanomolar sensitivities to their activating ligands mandipropamid and azinphos-ethyl. Experiments in Arabidopsis thaliana and Saccharomyces cerevisiae demonstrate the sensitive detection of banned organophosphate contaminants using living biosensors and the construction of multi-input/output genetic circuits. Our new modules enable ligand-programmable multi-channel CID systems for plant and eukaryotic synthetic biology that can empower new plant-based and microbe-based sensing modalities.

Triclosan, like many other aromatic halides, plays an important role industrially and inevitably ends up in the environment. Chemical treatments have effectively mitigated the presence of such chemicals, through using harsh oxidizing treatments, which are not without issues. A milder and greener alternative, such as an electrochemical method, is needed for the mitigation of compounds, such as triclosan. Herein, we evaluated triclosan treatment via electrochemical cycling and compared it to a traditional chemical oxidative process. Cyclic voltammetry was carried out using a three-electrode cell containing glassy carbon, silver wire, and platinum wire in organic solvent. Electrochemical cycling revealed 6 × greater triclosan conversion compared to traditional chemical oxidation reaction, as monitored by UV–Vis spectroscopy. In terms of reaction product selectivity, the chemical and electrochemical reactions yielded the oxidized triclosan and an ether cleavage product, dichlorophenol, as determined by gas chromatography–mass spectrometry. Of note, the chemical oxidation yielded the chlorinated re-dimerization side product, which was not observed during electrochemical cycling, which is beneficial, as such products have to be degraded again. Overall, our findings indicate that electrochemical methods offer significant advantages over traditional organic methods, such as product selectivity, relative conversion, and greener operation. In addition, electrochemical approaches offer tunability, such as electrode material, electrolyte, solvent, potential, or current applied, all of which may be integrated into a more efficient environmental application. [ABSTRACT FROM AUTHOR]

N‐substituted pyridino‐based congeners of Ebselen, named here as Pyrselen, incorporating proximal Se and N atoms, undergo dimerization in solution and the solid state through a dual donor‐acceptor arrangement of chalcogen bonding sites. Dimerization constants were measured within the 5–50 M−1 range. Computational studies on the dimers depict a notable charge‐transfer contribution to the association, validating Pyrselen as an effective scaffold for designing chalcogen‐bonding‐based recognition motifs. [ABSTRACT FROM AUTHOR]

Mastering of analytical methods for accurate quantitative determinations of enantiomeric excess is a crucial aspect in asymmetric catalysis, chiral synthesis, and pharmaceutical applications. In this context, the phenomenon of Self‐Induced Diastereomeric Anisochronism (SIDA) can be exploited in NMR spectroscopy for accurate determinations of enantiomeric composition, without using a chiral auxiliary that could interfere with the spectroscopic investigation. This phenomenon can be particularly useful for improving the quantitative analysis of mixtures with low enantiomeric excesses, where direct integration of signals can be tricky. Here, we describe a novel analysis protocol to correctly determine the enantiomeric composition of scalemic mixtures and investigate the thermodynamic and stereochemical features at the basis of SIDA. Dipeptide derivatives were chosen as substrates for this study, given their central role in drug design. By integrating the experiments with a conformational stochastic search that includes entropic contributions, we provide valuable information on the dimerization thermodynamics, the nature of non‐covalent interactions leading to self‐association, and the differences in the chemical environment responsible for the anisochronism, highlighting the importance of different stereochemical arrangement and tight association for the distinction between homochiral and heterochiral adducts. An important role played by the counterion was pointed out by computational studies. [ABSTRACT FROM AUTHOR]

Ethylene dimerization is an industrial process that is currently carried out using homogeneous catalysts. Here we present a highly active heterogeneous catalyst containing minute amounts of atomically dispersed Pd. It requires no co‐catalyst(s) or activator(s) and significantly outperforms previously reported catalysts tested under similar reaction conditions. The selectivity to C4‐ and C6‐hydrocarbons was about 80 % and 10 % at 42 % ethylene conversion at 200 °C using an industrially relevant feed containing 50 vol % ethylene, respectively. Our kinetic and catalyst characterization experiments complemented by density functional theory calculations provide molecular insights into the local environment of isolated Pd(II)Ox species and their role in achieving high activity in the target reaction. When the developed catalyst was rationally integrated with a Mo‐containing olefin metathesis catalyst in the same reactor, the formed butenes reacted with ethylene to propylene with a selectivity of 98 % at about 24 % ethylene conversion. [ABSTRACT FROM AUTHOR]

Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans -autoactivation via EED, suggesting a previously unknown mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification-coupled dimerization in the regulation of chromatin-modifying complexes. [Display omitted] • Human PRC2 dimerizes asymmetrically while bound to nucleosomes • The nucleosome-proximal PRC2 is allosterically activated by the other PRC2 via EED • Dimerization-driven stimulation is mediated by automethylated EZH2 K510 • Allosteric dimerization affects context-dependent PRC2 function The multi-protein complex PRC2 is a transcriptional regulator that trimethylates lysine 27 of histone H3 (H3K27me3) upon EED-dependent allosteric activation. Here, using cryo-electron microscopy and functional assays, Sauer et al. show that PRC2 dimerization on chromatin enables stimulation via automethylated EZH2 binding to EED, enabling PRC2 activity independent of other activators. [ABSTRACT FROM AUTHOR]

Polyampholytes (PAs) exhibit complex behaviors in various environments influenced by their charge distribution. This study focuses on the kinetics of dimerization of PAs, aiming to elucidate the underlying mechanisms and clarify relevant characteristics of the charge sequence. We focus on PAs with non-zero net charges, employing molecular dynamics simulations and theoretical analyses to examine how charge sequences influence the rates of dimer formation and dissociation. Our findings reveal that the charge sequence of tails and the blockiness of the minority charge group markedly influence the kinetics of dimerization: large blockiness and tails with a high number of majority-type charges slow down the dissociation of dimers. Additionally, the presence of an extended (central) block of the majority charge promotes structural diversity. Within dimer states, blocks alternate between intra- and inter-chain contacts. The duration times in the dimer states are significantly longer than the typical dwell times of block inter-contacts, with a notable extension when multiple blocks are engaged. Intrinsically disordered proteins (IDPs) play crucial roles in cellular functions, primarily due to their ability to undergo rapid conformational changes and form transient complexes. These properties largely depend on the sequence of charged residues. We provide insights into the fundamental principles governing the structural and dynamical properties of polyampholytic IDP, emphasizing the importance of sequence-specific effects on both aggregation and dissociation. [ABSTRACT FROM AUTHOR]

RAS proteins are peripheral membrane GTPases that activate multiple downstream effectors for cell proliferation and differentiation. The formation of a signaling RAS–RAF complex at the plasma membrane is implicated in a quarter of all human cancers; however, the underlying mechanism remains unclear. In this work, nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses to determine the structure of a hetero‐tetrameric complex comprising KRAS and the RAS‐binding domain (RBD) and cysteine‐rich domain (CRD) of activated RAF1 are employed. The binding of the RBD or RBD–CRD differentially alters the dimerization modes of KRAS on both anionic and neutral membranes, validated by interface‐specific mutagenesis. Notably, the RBD binding allosterically generated two distinct KRAS dimer interfaces in equilibrium, favored by KRAS free and in complex with the RBD–CRD, respectively. Additional interactions of the CRD with both KRAS protomers are mutually cooperative to stabilize a new dimer configuration of KRAS bound to the RBD–CRD. The RAF binding sequentially alters KRAS dimerization, providing new insights into RAF activation, including a configurational transition of the KRAS dimer to provide an interaction site for the CRD and release the autoinhibited RAF complex. These methods are applicable to many other signaling protein complexes on the membrane. [ABSTRACT FROM AUTHOR]

The issue of counterfeiting has always been a major challenge in today's society, putting forward high requirements for anti‐counterfeiting technology. Here, a promising 2D/3D anti‐counterfeiting security system is developed based on anthracene‐functionalized poly(styrene‐butadiene‐styrene) (SBS‐CAN), which possessed the physical unclonable self‐wrinkling patterns, fluorescence, and shape memory behavior. By controlling the dimerization of anthracene groups with ultraviolet light and external pre‐stretched operation, 2D information with surface wrinkle and fluorescence is achieved, allowing for the design of security systems based on actual needs. Furthermore, 3D structures constructed based on the shape memory behavior can further be utilized to encrypt these 2D information, enhancing the security level and weakening the cloneable risk of surface wrinkle and fluorescence for further. This programmable 2D/3D anti‐counterfeiting system has multiple advantages over the commonly used fluorescent wrinkled tag or fluorescent shape memory label, providing an intelligent choice for high‐security information carriers. [ABSTRACT FROM AUTHOR]

Bioactive dimeric (pre‐)anthraquinones are ubiquitous in nature and are found in bacteria, fungi, insects, and plants. Their biosynthesis via oxidative phenol coupling (OPC) is catalyzed by cytochrome P450 enzymes, peroxidases, or laccases. While the biocatalysis of OPC in molds (Ascomycota) is well‐known, the respective enzymes in mushroom‐forming fungi (Basidiomycota) are unknown. Here, we report on the biosynthesis of the atropisomers phlegmacin A1 and B1 of the mushroom Cortinarius odorifer. The biosynthesis of these unsymmetrically 7,10'‐homo‐coupled dihydroanthracenones was heterologously reconstituted in the mold Aspergillus niger. Methylation of the parental monomer atrochrysone to its 6‐O‐methyl ether torosachrysone by the O‐methyltransferase CoOMT1 precedes the regioselective homocoupling to phlegmacin, catalyzed by the enzyme CoUPO1 annotated as an "unspecific peroxygenase" (UPO). Our results reveal an unprecedented UPO reaction, thereby expanding the biocatalytic portfolio of oxidative phenol coupling beyond the commonly reported enzymes. The results show that Basidiomycota use peroxygenases to selectively couple aryls independently of and convergently to any other group of organisms, emphasizing the central role of OPC in natural processes. [ABSTRACT FROM AUTHOR]

A comprehensive investigation of two new molecular triads incorporating the diketopyrrolopyrrole unit into a quinoidized thienothiophene skeleton, which is further end‐capped with dicyanomethylene (DPP‐TT‐CN) or phenoxyl groups (DPP‐TT‐PhO), has been carried out. A combination of UV‐Vis‐NIR and infrared spectroelectrochemical techniques and cryogenic UV‐Vis‐NIR absorption spectroscopy supported by theoretical calculations has been used. The main result is the formation of similar H‐aggregates in the dimerization process of the neutral molecules and of the charged anionic species. The experimental absorption spectra of the aggregated species are accurately reproduced by quantum chemical calculations using the Spano's model, including excitonic coupling for the dimeric forms and full vibronic resolution of the absorption bands. The strong excitonic coupling taking place is key to understand the electronic structure of the dimeric species and has been instrumental to disentangle the type of H‐aggregation. This study is of relevance to get a better understanding of the molecular aggregation of organic π‐conjugated chromophores and is useful as a guideline for the refinement of the engineering of molecular materials for which supramolecular design is required. [ABSTRACT FROM AUTHOR]

We demonstrate that 2‐alkenylarylaldimines and ketimines undergo thermal 6π‐azaelectrocyclization to generate a wide range of azabicyclic o‐quinodimethanes (o‐QDMs). These o‐QDMs exist as a hybrid of a diene and a benzylic diradical. The diradical nature was confirmed by their ability to undergo dimerization and react with H‐atom donor, 2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) and O2. In addition, the interception of the diradicaloid o‐QDMs by H‐atom transfer was used to synthesize five tetrahydroisoquinoline alkaloids and related bioactive molecules. The diene form can undergo [4+2] cycloaddition reactions with different dienophiles to generate bridged azabicycles in high endo:exo selectivity. The azabicyclic o‐QDMs can be generated for [4+2] cycloaddition from a wide range of electronically and sterically varied 2‐alkenylarylimines, including mono, di, tri and tetrasubstituted alkenes, and imines derived from arylamine, alkylamine (1°, 2°, 3°), benzylamine, benzylsulfonamide and Boc‐amine. [ABSTRACT FROM AUTHOR]

Herein the reaction of methy cinnamates with N‐Iodosuccinimide (NIS) is reported and the possible formation of dihydrobenzofuryl dimeric derivatives (DHBF), known for their biological activities, is explored. Having an oxidizing capacity, we studied the behavior of NIS with methyl ferulate and under optimized reaction conditions we obtained its DHBF dimer in 35% yield. It is worth to note that we did not obtain the DHBF in his natural form, but rather as the demethylated compound, likely due to dismutation reactions activated by the presence of water in the solvent. Methyl caffeate reacted with NIS to furnish the DHBF dimer in 15% yield, while methyl coumarate and methyl isoferulate did not give any form of DHBF dimers, showing the importance of a hydroxyl group in para position on an activated system and an electron‐rich aromatic ring. An electrochemical investigation by cyclic voltammetry was carried out on the three cinnamates and confirmed the correlation between dimerization and oxidation potential: methyl ferulate and methyl caffeate dimerize, while methyl coumarate, due to its higher oxidizing potential, does not. [ABSTRACT FROM AUTHOR]

Polymerization of primary amine‐containing monomers is challenging because the amine inhibits polymerization catalyst activity. An alternative approach to access primary amine functionalized polymers is postpolymerization modification. To this end, the hydroaminoalkylation of vinyl‐terminated polyolefins with N‐(trimethylsilyl)benzylamine is used to prepare primary amine‐terminated polyolefins, with the free primary amine substituent being revealed upon hydrolytic work up. These materials are spectroscopically characterized, and an investigation of thermal properties by differential scanning calorimetry and thermogravimetric analysis is completed. These results show that the primary amine substituent increases the glass transition temperature and improves thermal stability. The reactive primary amine functionality is used in the photo‐oxidative dimerization of polyolefins to demonstrate how this elusive functionality can be applied in oligomer valorization. [ABSTRACT FROM AUTHOR]

This work conducts a comprehensive theoretical study on the non‐covalent complexation between cyclocarbons and C60 fullerene for the first time. The binding energy between cyclocarbons and C60 fullerene is significantly stronger than that between two C18 or two C60 fullerenes, indicating a particularly strong affinity. The cyclocarbons and C60 fullerene can spontaneously assemble into complexes in the gas phase at room temperature, and the hydrophobic effect caused by the solvent environment can promote this binding. The binding strength with C60 fullerene increases almost linearly with the increase of cyclocarbon size, and the C34@C60 dimer exhibits a perfect nano‐Saturn structure. As the ring size increases, the angle between the two cyclocarbons of the 2 : 1 trimers formed by cyclocarbons and C60 fullerene gradually decreases. In C60@2 C34 trimer, the fullerene is symmetrically surrounded by two cyclocarbons. The results on the trimers formed by cyclocarbon and C60 fullerenes in a 1 : 2 ratio showed when the cyclocarbon sandwiched between two fullerenes is not quite large, the trimers exhibit an ideal dumbbell‐like structure, and the presence of the first fullerene has a significant synergistic effect on the binding of the second one. The cyclocarbon greatly promotes the dimerization of fullerenes, which acted as a "molecular glue". [ABSTRACT FROM AUTHOR]

Most albumin in blood plasma is thought to be monomeric with some 5% covalently dimerized. However, many reports in the recent biophysics literature find that albumin is reversibly dimerized or even oligomerized. We review data on this from X‐ray crystallography and diverse biophysical techniques. The number‐average molecular weight of albumin would be increased by dimerization, affecting size‐dependent filtration processes of albumin such as at the glycocalyx of the capillary endothelium and the podocyte slit‐diaphragm of the renal glomerulus. If correct, and depending on characteristics of the process, such as Kd, reversible dimerization of albumin in plasma would have major implications for normal physiology and medicine. We present quantitative models of the impact of dimerization on albumin molecular forms, on the number‐average molecular weight of albumin, and estimate the effect on the colloid osmotic pressure of albumin. Dimerization reduces colloid osmotic pressure as total albumin concentration increases below that expected in the absence of dimerization. Current models of albumin filtration by the renal glomerulus would need revision to account for the dynamic size of albumin molecules filtered. More robust biophysical data are needed to give a definitive answer to the questions posed and we suggest possible approaches to this. What is the central question of this study?Is there reversible dimerization of albumin in blood plasma? Albumin in blood plasma is generally considered monomeric apart from a small proportion of covalent dimer, but recent reports suggest it may actually be reversibly dimerized: is this physiologically significant?What is the main finding and its importance?There is some evidence that fatty acid‐free albumin dimerizes but less for native albumin. Dimerization, if proven, requires revision of the current molecular concepts underlying observed colloid osmotic pressures of plasma and renal ultrafiltration of albumin. Biophysical evidence for dimerization in plasma is currently weak. [ABSTRACT FROM AUTHOR]

An analytic solution is presented for the simultaneous substrate elimination problem that combines Michaelis-Menten (MM) consumption with an irreversible homo-dimerization process. The implicit solution involves logarithm and inverse tangent functions and perfectly agrees with the numerical solution of the differential equation. A solution is also presented for the generalized dynamical problem that simultaneously combines MM kinetics with first and second-order processes. The exact expressions for the half-life and the area under the curve are also presented for these problems. [ABSTRACT FROM AUTHOR]

Herein, we disclose the first reports on the utilization of vinylene carbonate as a C1 methylene source in ruthenium-catalyzed additive controlled regioselective C4-methylenation and weak chelation-assisted C8-formylmethylation of isoquinolinones. Adopting vinylene carbonate as both a C2 and C1 synthon is an important highlight of this work. Amide carbonyl acts as the traceless directing group in C8-formylmethylation. Remarkably, in this reaction, two C–C bonds form in one-pot producing dimeric isoquinolinones by employing vinylene carbonate as a methylene surrogate in the presence of copper acetate as an additive. Importantly, unsymmetrical dimers were achievable, albeit in low yield. Extensive control experiments are conducted to decipher the reaction mechanism. It is evident from the mechanistic studies, that the formation of a formylmethyl group in situ at the C4-carbon undergoes dimerization, oxidation and subsequent decarboxylation to produce methylene-bridged isoquinolinone dimers. This protocol is scalable and compatible with a repertoire of substrates and shows high functional group tolerance. Harnessing vinylene carbonate as both a C2 and C1 synthon is an important highlight of this work. [ABSTRACT FROM AUTHOR]

The electrochemical oxidative phenol coupling reaction is a sustainable method for accessing biphenolic compounds. Using the dimerization of sesamol as a model reaction, insights into the reaction mechanism were gained via operando Raman spectroscopy. By varying the solvent and electrodes, different reaction mechanisms were identified and correlated with the respective product yields. [ABSTRACT FROM AUTHOR]

New proteasomes are produced to accommodate increases in cellular catabolic demand and prevent the accumulation of cytotoxic proteins. Formation of the proteasomal 20S core complex relies on the function of the five chaperones PAC1-4 and POMP. Here, to understand how these chaperones facilitate proteasome assembly, we tagged the endogenous chaperones using CRISPR/Cas gene editing and examined the chaperone-bound complexes by cryo-EM. We observe an early α-ring intermediate subcomplex that is stabilized by PAC1-4, which transitions to β-ring assembly upon dissociation of PAC3/PAC4 and rearrangement of the PAC1 N-terminal tail. Completion of the β-ring and dimerization of half-proteasomes repositions critical lysine K33 to trigger cleavage of the β pro-peptides, leading to the concerted dissociation of POMP and PAC1/PAC2 to yield mature 20S proteasomes. This study reveals structural insights into critical points along the assembly pathway of the human proteasome and provides a molecular blueprint for 20S biogenesis. Cellular proteostasis requires the replenishment of proteasomes. Here the authors use CRISPR/Cas gene editing and cryo-EM to visualize the stepwise assembly of the human 20S proteasome. [ABSTRACT FROM AUTHOR]

Oleanolic acid, a naturally occurring triterpenoid compound, has garnered significant attention in the scientific community due to its diverse pharmacological properties. Continuing our previous work on the synthesis of oleanolic acid dimers (OADs), a simple, economical, and safe acetylation reaction was performed. The newly obtained derivatives (AcOADs, 3a–3n) were purified using two methods. The structures of all acetylated dimers (3a–3n) were determined based on spectral methods (IR, NMR). For all AcOADs (3a–3n), the relationship between the structure and the expected directions of pharmacological activity was determined using a computational method (QSAR computational analysis). All dimers were also tested for their cytotoxic activity on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines. HDF cell line was applied to evaluate the Selectivity Index of the tested compounds. All cytotoxic tests were performed with the application of the MTT assay. Finally, all dimers of oleanolic acid were subjected to DPPH and CUPRAC tests to evaluate their antioxidant activity. The obtained results indicate a very high level of cytotoxic activity (IC50 for most AcOADs below 5.00 µM) and a fairly high level of antioxidant activity (Trolox equivalent in some cases above 0.04 mg/mL). [ABSTRACT FROM AUTHOR]

Truncating genetic variants of SORL1, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in SORL1 are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which the SORL1 coding missense variant rs772677709, that leads to a p.Y1816C substitution, segregates with Alzheimer's disease. Further, we investigate the effect of SORLA p.Y1816C on receptor maturation, cellular localization, and trafficking in cell-based assays. Under physiological circumstances, SORLA dimerizes within the endosome, allowing retromer-dependent trafficking from the endosome to the cell surface, where the luminal part is shed into the extracellular space (sSORLA). Our results showed that the p.Y1816C mutant impairs SORLA homodimerization in the endosome, leading to decreased trafficking to the cell surface and less sSORLA shedding. These trafficking defects of the mutant receptor can be rescued by the expression of the SORLA 3Fn-minireceptor. Finally, we find that iPSC-derived neurons with the engineered p.Y1816C mutation have enlarged endosomes, a defining cytopathology of AD. Our studies provide genetic as well as functional evidence that the SORL1 p.Y1816C variant is causal for AD. The partial penetrance of the mutation suggests this mutation should be considered in clinical genetic screening of multiplex early-onset AD families. [ABSTRACT FROM AUTHOR]

We generated SARS-CoV-2 variants resistant to three SARS-CoV-2 main protease (Mpro) inhibitors (nirmatrelvir, TKB245, and 5h), by propagating the ancestral SARS-CoV-2WK521WT in VeroE6TMPRSS2 cells with increasing concentrations of each inhibitor and examined their structural and virologic profiles. A predominant E166V-carrying variant (SARS-CoV-2WK521E166V), which emerged when passaged with nirmatrelvir and TKB245, proved to be resistant to the two inhibitors. A recombinant SARS-CoV-2E166V was resistant to nirmatrelvir and TKB245, but sensitive to 5h. X-ray structural study showed that the dimerization of Mpro was severely hindered by E166V substitution due to the disruption of the presumed dimerization-initiating Ser1'-Glu166 interactions. TKB245 stayed bound to MproE166V, whereas nirmatrelvir failed. Native mass spectrometry confirmed that nirmatrelvir and TKB245 promoted the dimerization of Mpro, and compromised the enzymatic activity; the Ki values of recombinant MproE166V for nirmatrelvir and TKB245 were 117±3 and 17.1±1.9 µM, respectively, indicating that TKB245 has a greater (by a factor of 6.8) binding affinity to MproE166V than nirmatrelvir. SARS-CoV-2WK521WT selected with 5h acquired A191T substitution in Mpro (SARS-CoV-2WK521A191T) and better replicated in the presence of 5h, than SARS-CoV-2WK521WT. However, no significant enzymatic or structural changes in MproA191T were observed. The replicability of SARS-CoV-2WK521E166V proved to be compromised compared to SARS-CoV-2WK521WT but predominated over SARS-CoV-2WK521WT in the presence of nirmatrelvir. The replicability of SARS-CoV-2WK521A191T surpassed that of SARS-CoV-2WK521WT in the absence of 5h, confirming that A191T confers enhanced viral fitness. The present data should shed light on the understanding of the mechanism of SARS-CoV-2's drug resistance acquisition and the development of resistance-repellant COVID-19 therapeutics. [ABSTRACT FROM AUTHOR]

The total syntheses of gochnatiolide D and ainsliadimer A were achieved through a streamlined one‐pot sequence starting from their biogenetic precursor dehydrozaluzanin C. These biomimetic, protecting group‐free syntheses involve the elegant orchestration of the highly diastereoselective hetero‐Diels‐Alder reaction of dehydrozaluzanin C, its subsequent hydrolysis to gochnatiolide D and finally an aldol reaction to ainsliadimer A, all harnessed by the hydrogen bond propensity and acidity of hexafluoroisopropanol (HFIP), which was utilized as the reaction solvent. [ABSTRACT FROM AUTHOR]

Excited‐state intramolecular proton transfer (ESIPT) chromophores have attracted considerable attention as promising gain media for organic lasers, particularly in amplified spontaneous emission (ASE) due to their advantageous characteristics. These include an intrinsic four‐level photocycle, significant separation between absorption and emission spectra, and enhanced emission efficiency facilitated by aggregate‐induced emission. This study investigates the amplification of π‐conjugation in hydroxyphenyl‐benzothiazole (HBT)‐based ESIPT materials via dimerization to intensify ESIPT processes, surge absorption cross‐section, enhance optical gain, and induce a redshift in emission spectra. Computational study shows that the ESIPT processes of the new dimers proceed through single proton transfer where the second proton transfer is not accessible. While the ESIPT photocycle does not extend to both HBT moieties of the dimers, the dimers foster more efficient ESIPT processes in both solution and solid states than their parent HBT, resulting in substantial Stokes shifts (>233 nm). Moreover, both dimers exhibit enhanced solid‐state photoluminescence quantum yields, reaching up to ≈55%, and low solid‐state ASE threshold values (≈6.8 µJ cm−2) in the red region. Remarkably, the new dimers demonstrate excellent thermal and photostability with notably reduced spectral overlap compared to their parent, highlighting the potential utility of the approaches to developing new organic solid‐state laser materials. [ABSTRACT FROM AUTHOR]

Many stimuli‐responsive materials harness the reversible association of supramolecular binding motifs to enable advanced functionalities such as self‐healing, switchable adhesion, or mechanical adaptation. Despite extensive research into the structure–property relationships of these materials, direct correlations between molecular‐level changes in supramolecular binding and macroscopic material behaviors have mostly remained elusive. Here, we show that this challenge can be overcome with supramolecular binding motifs featuring integrated binding indicators. We demonstrate this using a novel motif that combines a hydrogen‐bonding ureido‐4‐pyrimidinone (UPy) with two strategically placed pyrene fluorophores. Dimerization of this motif promotes pyrene excimer formation, facilitating the straightforward optical quantification of supramolecular assembly under various conditions. We exploit the new motif as a supramolecular cross‐linker in poly(methyl acrylate)s to probe the extent of (dis)assembly as a function of cross‐linker content, processing history, and applied stimuli. We demonstrate that the stimuli‐induced dissociation of hydrogen‐bonding linkages strongly depends on the initial cross‐link density, which also dictates whether the force‐induced dissociation in polymer films correlates with the applied stress or strain. Thus, beyond introducing a robust tool for the in situ study of dynamic (dis)assembly mechanisms in supramolecular systems, our findings provide new insights into the mechanoresponsive behavior of such materials. [ABSTRACT FROM AUTHOR]

The dimerization of small molecule acceptors (SMAs) holds significant potential by combining the advantages of both SMAs and polymer acceptors in realizing high power conversion efficiency (PCE) and operational stability in organic solar cells (OSCs). However, advancements in the selection and innovation of dimeric linkers are still challenging in enhancing their performance. In this study, three new dimeric acceptors, namely DY‐Ar‐4, DY‐Ar‐5, and DY‐Ar‐6 are synthesized, by linking two Y‐series SMA subunits via an “end‐to‐end” strategy using flexible spacers (octyl, decyl, and dodecyl, respectively). The influence of spacer lengths on device performance is systematically investigated. The results indicate that DY‐Ar‐5 exhibits more compact and ordered packing, leading to an optimal morphology. OSCs based on PM6: DY‐Ar‐5 achieves a maximum PCE of 15.76%, attributes to enhance and balance carrier mobility, and reduce carrier recombination. This dimerization strategy using suitable non‐conjugated linking units provides a rational principle for designing high‐performance non‐fullerene acceptors. [ABSTRACT FROM AUTHOR]

The opening of the mitochondrial permeability transition pore (PTP), a Ca2+‐dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP‐induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F‐ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3‐induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense. [ABSTRACT FROM AUTHOR]

The inhibitor of κB (IκB) kinase (IKK) is a central regulator of NF-κB signaling. All IKK complexes contain hetero- or homodimers of the catalytic IKKβ and/or IKKα subunits. Here, we identify a YDDΦxΦ motif, which is conserved in substrates of canonical (IκBα, IκBβ) and alternative (p100) NF-κB pathways, and which mediates docking to catalytic IKK dimers. We demonstrate a quantitative correlation between docking affinity and IKK activity related to IκBα phosphorylation/degradation. Furthermore, we show that phosphorylation of the motif's conserved tyrosine, an event previously reported to promote IκBα accumulation and inhibition of NF-κB gene expression, suppresses the docking interaction. Results from integrated structural analyzes indicate that the motif binds to a groove at the IKK dimer interface. Consistently, suppression of IKK dimerization also abolishes IκBα substrate binding. Finally, we show that an optimized bivalent motif peptide inhibits NF-κB signaling. This work unveils a function for IKKα/β dimerization in substrate motif recognition. The inhibitor of kB kinase (IKK) is a central regulator of NF-kB signalling. Here the authors identify a motif conserved in substrates of canonical and alternative NF-kB pathways which mediates docking to catalytic IKK dimers: they show that phosphorylation of the conserved tyrosine suppresses the docking interaction. [ABSTRACT FROM AUTHOR]

WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction. Here the authors report the cryo-EM structure of Frizzeled 4 in complex with the DEP domain of Dishevelled 2. The study unveils the key mechanism of WNT signalling activation, the recruitment of dishevelled to Frizzled receptor. [ABSTRACT FROM AUTHOR]

The organic compound 7–hydroxy–4–methyl coumarin, also known as 4–methylumbelliferone or hymecromone, belongs to the lactone family. The compound's molecular geometry, the bond angle, and the bond length of its dimers were determined by theoretical calculations using the software packages Gaussian 09W and Multiwfn 3.8. The most stable form of the 7–hydroxyl–4–methyl coumarin molecule is found to be a syn-ht dimer with an energy of −1223.1466 (a.u.).VEDA 4 software was used to determine vibrational assignments and PED values to gain insight into the structural details of these dimers. The vibrations of dimers formed from the same monomer showed remarkable differences. To support the chemical reactivity of the dimers, the HOMO–LUMO energy gap, MEP, and ALIE maps were analyzed. The anti-hh dimer was found to be highly polarizable and reactive in both solvent and gaseous media. In addition, Fukui functions were used to analyze the electrophilic (E +) and nucleophilic (Nu-) sites. The electronic excitation and UV–vis spectra were predicted using the time–dependent density functional theory (DFT) method. RDG-NCI and AIM analyses were utilized for predicting weak interactions between dimer molecules. Electronic parameters such as density of states (DOS) analysis, transition density matrix (TDM), and energy levels of electrons and holes were also analyzed. Based on the theoretical analysis, it is evident that this particular molecule exhibits a propensity for dimerization, with the resulting dimers showing considerable potential for advancement in various fields, particularly in the field of polymers and materials. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) triggers a severe systemic inflammatory reaction in mammals, with the dimerization of TLR4/MD-2 upon LPS stimulation serving as the pivotal mechanism in the transmission of inflammatory signals. Ginsenoside Rh2 (G-Rh2), one of the active constituents of red ginseng, exerts potent anti-inflammatory activity. However, whether G-Rh2 can block the TLR4 dimerization to exert anti-inflammatory effects remains unclear. Here, we first investigated the non-cytotoxic concentration of G-Rh2 on RAW 264.7 cells, and detected the releases of pro-inflammatory cytokines in LPS-treated RAW 264.7 cells, and then uncovered the mechanisms involved in the anti-inflammatory activity of G-Rh2 through flow cytometry, fluorescent membrane localization, Western blotting, co-immunoprecipitation (Co-IP), molecular docking and surface plasmon resonance (SPR) analysis in LPS-stimulated macrophages. Our results show that G-Rh2 stimulation markedly inhibited the secretion of LPS-induced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Additionally, G-Rh2 blocked the binding of LPS with the membrane of RAW 264.7 cells through direct interaction with TLR4 and MD-2 proteins, leading to the disruption of the dimerization of TLR4 and MD-2, followed by suppression of the TLR4/NF-κB signaling pathway. Our results suggest that G-Rh2 acts as a new inhibitor of TLR4 dimerization and may serve as a promising therapeutic agent against inflammation. [ABSTRACT FROM AUTHOR]

Simple Summary: The inactivation of apoptotic signaling by inhibitors of apoptosis proteins (IAPs) is one of the important hallmarks of cancer cells. Survivin, a 16.5 kDa member of the IAP family, is commonly enriched in many cancers and is a potential therapeutic target. We investigated the Survivin-targeting potential of Withaferin-A (Wi-A) and Withanone (Wi-N), two major withanolides from Withania somnifera (Ashwagandha), using computational assays. The results were validated in various in vitro experimental assays using Wi-A-rich extracts from Ashwagandha leaves, suggesting their use as an important bioresource for cancer drug development. Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to the high cost and adverse side effects of synthetic drugs, natural compounds with similar activity have also been in demand. In this study, we conducted molecular docking assays to evaluate the ability of Wi-A and Wi-N to block Survivin dimerization. We found that Wi-A, but not Wi-N, can bind to and prevent the homodimerization of Survivin, similar to YM-155. Therefore, we prepared a Wi-A-rich extract from Ashwagandha leaves (Wi-AREAL). Experimental analyses of human cervical carcinoma cells (HeLa and ME-180) treated with Wi-AREAL (0.05–0.1%) included assessments of viability, apoptosis, cell cycle, migration, invasion, and the expression levels (mRNA and protein) of molecular markers associated with these phenotypes. We found that Wi-AREAL led to growth arrest mediated by the upregulation of p21WAF1 and the downregulation of several proteins (CDK1, Cyclin B, pRb) involved in cell cycle progression. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial–mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment. [ABSTRACT FROM AUTHOR]

In the title compound, bis[aqua(2,2′-bipyridine) fluoridotin (II)] hexafluoridotin(IV), [SnF(C10H8N2)(H2O)]2[SnF6], an ionic mixed-valent tin(II)–tin(IV) compound, the bivalent tin atom is the center atom of the cation and the tetravalent tin atom is the center atom of the anion. With respect to the first coordination sphere, the cation is monomeric, with the tin(II) atom having a fourfold seesaw coordination with a fluorine atom in an equatorial position, a water molecule in an axial position and the two nitrogen atoms of the chelating 2,2′-bipyridine ligand in the remaining axial and equatorial positions. The bond lengths and angles of this hypervalent first coordination sphere are described by 2c–2e and 3c–4e bonds, respectively, all of which are based on the orthogonal 5p orbitals of the tin atom. In the second coordination sphere, which is based on an additional, very long tin–fluorine bond that leads to dimerization of the cation, the tin atom is trapezoidal–pyramidally coordinated. The tetravalent tin atom of the centrosymmetric anion has an octahedral coordination. The differences in its tin–fluorine bond lengths are attributed to hydrogen bonding, as the two of the four fluorine atoms are each involved in two hydrogen bonds, linking anions and cations together to form strands. [ABSTRACT FROM AUTHOR]

Indocyanine green (ICG), the only near-infrared (NIR) dye approved for clinical use, has received increasing attention as a theranostic agent wherein diagnosis (fluorescence) is combined with therapy (phototherapy), but suffers rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here we report that dimerized ICG can self-assemble to form zwitterionic nanoparticles (ZN-dICG), which generate fluorescence self-quenching but exhibit superior photothermal and photodynamic properties over ICG. The zwitterionic moieties confer ZN-dICG an ultralow critical micelle concentration and high colloidal stability with low non-specific binding in vivo. In addition, ZN-dICG can respond to the over-generated reactive oxygen species (ROSs) and dissociate to restore NIR fluorescence of ICG, amplifying the sensitivity via albumin binding for low-background imaging of tumors. Following systemic administration, ZN-dICG accumulated in tumors of xenograft-bearing mice for imaging primary and metastatic tumors, and induced tumor ablation under laser irradiation. The discovery of ZN-dICG would contribute to the design of translational phototheranostic platform with high biocompatibility. Indocyanine green (ICG) has been extensively studied as a phototheranostic agent that combines imaging with phototherapies, but it suffers from rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here, we report a strategy to construct ICG dimers (ICG-tk-ICG) by conjugating two ICG molecules via a thioketal bond, which can self-assemble into zwitterionic nanoparticles (ZN-dICG) at ultralow critical micelle concentrations, exhibiting superior photothermal and photodynamic properties over ICG. ZN-dICG responds to the over-generated ROS in tumors and dissociates to restore the NIR fluorescence of ICG, enhancing the sensitivity via albumin binding for low-background imaging of tumors. This study offers a supramolecular strategy that may potentiate the clinical translation of ICG in imaging-guided cancer phototherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Redox flow battery shows promise for grid-scale energy storage. Aqueous organic redox flow batteries are particularly popular due to their potentially low material cost and safe water-based electrolyte. Commonly, redox active molecules used in this field feature aromatic rings, and increasing π -aromatic conjugation has been a popular strategy to achieve high energy density, high power density, and reduced crossover in new material design. However, this approach can inadvertently hinder redox activity depending on redox mechanism. This study reveals the underlying π - π stacking effect in extended aromatic redox active compounds, where aromatic radical intermediates are involved in the redox process. We report a molecular design strategy to mitigate the negative effect of π - π stacking by altering solvation dynamics and introducing molecular steric hindrance. [ABSTRACT FROM AUTHOR]

The Arabidopsis CROWDED NUCLEI (CRWN) family proteins form a lamina-like meshwork beneath the nuclear envelope with multiple functions, including maintenance of nuclear morphology, genome organization, DNA damage repair and transcriptional regulation. CRWNs can form homodimers/heterodimers through protein‒protein interactions; however, the exact molecular mechanism of CRWN dimer formation and the diverse functions of different CRWN domains are not clear. In this report, we show that the N-terminal coiled-coil domain of CRWN1 facilitates its homodimerization and heterodimerization with the coiled-coil domains of CRWN2–CRWN4. We further demonstrated that the N-terminus but not the C-terminus of CRWN1 is sufficient to rescue the defect in nuclear morphology of the crwn1 crwn2 mutant to the WT phenotype. Moreover, both the N- and C-terminal fragments of CRWN1 are necessary for its normal function in the regulation of plant development. Collectively, our data shed light on the mechanism of plant lamina network formation and the functions of different domains in plant lamin-like proteins. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptors (mGluRs) are dimeric class C G-protein-coupled receptors that operate in glia and neurons. Glutamate affinity and efficacy vary greatly between the eight mGluRs. The molecular basis of this diversity is not understood. We used single-molecule fluorescence energy transfer to monitor the structural rearrangements of activation in the mGluR ligand binding domain (LBD). In saturating glutamate, group II homodimers fully occupy the activated LBD conformation (full efficacy) but homodimers of group III mGluRs do not. Strikingly, the reduced efficacy of Group III homodimers does not arise from differences in the glutamate binding pocket but, instead, from interactions within the extracellular dimerization interface that impede active state occupancy. By contrast, the functionally boosted mGluR II/III heterodimers lack these interface brakes to activation and heterodimer asymmetry in the flexibility of a disulfide loop connecting LBDs greatly favors occupancy of the activated conformation. Our results suggest that dimerization interface interactions generate substantial functional diversity by differentially stabilizing the activated conformation. This diversity may optimize mGluR responsiveness for the distinct spatio-temporal profiles of synaptic versus extrasynaptic glutamate.

Abstract Most albumin in blood plasma is thought to be monomeric with some 5% covalently dimerized. However, many reports in the recent biophysics literature find that albumin is reversibly dimerized or even oligomerized. We review data on this from X‐ray crystallography and diverse biophysical techniques. The number‐average molecular weight of albumin would be increased by dimerization, affecting size‐dependent filtration processes of albumin such as at the glycocalyx of the capillary endothelium and the podocyte slit‐diaphragm of the renal glomerulus. If correct, and depending on characteristics of the process, such as Kd, reversible dimerization of albumin in plasma would have major implications for normal physiology and medicine. We present quantitative models of the impact of dimerization on albumin molecular forms, on the number‐average molecular weight of albumin, and estimate the effect on the colloid osmotic pressure of albumin. Dimerization reduces colloid osmotic pressure as total albumin concentration increases below that expected in the absence of dimerization. Current models of albumin filtration by the renal glomerulus would need revision to account for the dynamic size of albumin molecules filtered. More robust biophysical data are needed to give a definitive answer to the questions posed and we suggest possible approaches to this.

The di(9-anthryl)methyl (DAntM) radical was synthesized and investigated to elucidate its optical, electrical properties, and reactivity. The generation of the DAntM radical was confirmed by its ESR spectrum, which showed two broad signals. The unpaired electron is primarily localized on the central sp2 carbon and slightly delocalized over the two anthryl moieties. Although the DAntM radical undergoes dimerization in solution, the radical still remains even at 190 K due to the bulky nature of the two anthryl groups. Interestingly, upon exposure to air, the purple color of the radical solution quickly fades to orange, resulting in decomposition to give 9-anthryl aldehyde and anthroxyl radical derivatives.

In the title compound, bis[aqua(2,2′-bipyridine)fluoridotin(II)] hexafluoridotin(IV), [SnF(C10H8N2)(H2O)]2[SnF6], an ionic mixed-valent tin(II)–tin(IV) compound, the bivalent tin atom is the center atom of the cation and the tetravalent tin atom is the center atom of the anion. With respect to the first coordination sphere, the cation is monomeric, with the tin(II) atom having a fourfold seesaw coordination with a fluorine atom in an equatorial position, a water molecule in an axial position and the two nitrogen atoms of the chelating 2,2′-bipyridine ligand in the remaining axial and equatorial positions. The bond lengths and angles of this hypervalent first coordination sphere are described by 2c–2e and 3c–4e bonds, respectively, all of which are based on the orthogonal 5p orbitals of the tin atom. In the second coordination sphere, which is based on an additional, very long tin–fluorine bond that leads to dimerization of the cation, the tin atom is trapezoidal–pyramidally coordinated. The tetravalent tin atom of the centrosymmetric anion has an octahedral coordination. The differences in its tin–fluorine bond lengths are attributed to hydrogen bonding, as the two of the four fluorine atoms are each involved in two hydrogen bonds, linking anions and cations together to form strands.

Purpose of Review: Disulfide bonds provide a convenient method for chemoselective alteration of peptide and protein structure and function. We previously reported that mild oxidation of a p53-derived bisthiol peptide (CTFANLWRLLAQNC) under dilute non-denaturing conditions led to unexpected disulfide-linked dimers as the exclusive product. The dimers were antiparallel, significantly α-helical, resistant to protease degradation, and easily reduced back to the original bisthiol peptide. Recent Findings: Here we examine the intrinsic factors influencing peptide dimerization using a combination of amino acid substitution, circular dichroism (CD) spectroscopy, and X-ray crystallography. CD analysis of peptide variants suggests critical roles for Leu6 and Leu10 in the formation of stable disulfide-linked dimers. The 1.0 Å resolution crystal structure of the peptide dimer supports these data, revealing a leucine-rich LxxLL dimer interface with canonical knobs-into-holes packing. Two levels of higher-order oligomerization are also observed in the crystal: an antiparallel “dimer of dimers” mediated by Phe3 and Trp7 residues in the asymmetric unit and a tetramer of dimers mediated by Trp7 and Leu10. In CD spectra of Trp-containing peptide variants, minima at 227 nm provide evidence for the dimer of dimers in dilute aqueous solution. Summary: Importantly, and in contrast to the original dimer model, the canonical leucine-rich core and robust dimerization of most peptide variants suggests a tunable molecular architecture to target various proteins and evaluate how folding and oligomerization impact various properties, such as cell permeability. [ABSTRACT FROM AUTHOR]

Transcription factors are multidomain proteins with specific DNA binding and regulatory domains. In the human FoxP subfamily (FoxP1, FoxP2, FoxP3, and FoxP4) of transcription factors, a 90 residue-long disordered region links a Leucine Zipper (ZIP)—known to form coiled-coil dimers—and a Forkhead (FKH) domain—known to form domain swapping dimers. We used replica exchange discrete molecular dynamics simulations, single-molecule fluorescence experiments, and other biophysical tools to understand how domain tethering in FoxP1 impacts dimerization at ZIP and FKH domains and how DNA binding allosterically regulates their dimerization. We found that domain tethering promotes FoxP1 dimerization but inhibits a FKH domain-swapped structure. Furthermore, our findings indicate that the linker mediates the mutual organization and dynamics of ZIP and FKH domains, forming closed and open states with and without interdomain contacts, thus highlighting the role of the linkers in multidomain proteins. Finally, we found that DNA allosterically promotes structural changes that decrease the dimerization propensity of FoxP1. We postulate that, upon DNA binding, the interdomain linker plays a crucial role in the gene regulatory function of FoxP1. [ABSTRACT FROM AUTHOR]

Abstract Copper chaperones of the ATX1 family are found in a wide range of organisms where these essential soluble carriers strictly control the transport of monovalent copper across the cytoplasm to various targets in diverse cellular compartments thereby preventing detrimental radical formation catalyzed by the free metal ion. Notably, the ATX1 family in plants contains two distinct forms of the cellular copper carrier. In addition to ATX1 having orthologs in other species, they also contain the copper chaperone CCH. The latter features an extra C-terminal extension whose function is still unknown. The secondary structure of this extension was predicted to be disordered in previous studies, although this has not been experimentally confirmed. Solution NMR studies on purified CCH presented in this study disclose that this region is intrinsically disordered regardless of the chaperone’s copper loading state. Further biophysical analyses of the purified metallochaperone provide evidence that the C-terminal extension stabilizes chaperone dimerization in the copper-free and copper-bound states. A variant of CCH lacking the C-terminal extension, termed CCHΔ, shows weaker dimerization but similar copper binding. Computational studies further corroborate the stabilizing role of the C-terminal extension in chaperone dimerization and identify key residues that are vital to maintaining dimer stability.

Abstract 12-oxophytodienoate reductase 3 (OPR3) is a key enzyme in the biosynthesis of jasmonoyl-L-isoleucine, the receptor-active form of jasmonic acid and crucial signaling molecule in plant defense. OPR3 was initially crystallized as a self-inhibitory dimer, implying that homodimerization regulates enzymatic activity in response to biotic and abiotic stresses. Since a sulfate ion is bound to Y364, mimicking a phosphorylated tyrosine, it was suggested that dimer formation might be controlled by reversible phosphorylation of Y364 in vivo. To investigate OPR3 homodimerization and its potential physiological role in more detail, we performed analytical gel filtration and dynamic light scattering on wild-type OPR3 and three variants (R283D, R283E, and Y364P). The experiments revealed a rapid and highly sensitive monomer–dimer equilibrium for all OPR3 constructs. We crystallized all constructs with and without sulfate to examine its effect on the dimerization process and whether reversible phosphorylation of Y364 triggers homodimerization in vivo. All OPR3 constructs crystallized in their monomeric and dimeric forms independent of the presence of sulfate. Even variant Y364P, lacking the putative phosphorylation site, was crystallized as a self-inhibitory homodimer, indicating that Y364 is not required for dimerization. Generally, the homodimer is relatively weak, and our results raise doubts about its physiological role in regulating jasmonate biosynthesis.

ERK1/2 is a key protein that mediates cell signal transduction, and it is involved in regulating biological processes such as chromatin remodeling, nuclear disintegration, proliferation, survival, metabolism, and cell migration and differentiation. Its overactivation is closely related to the occurrence and progression of cancer, and the mechanism is manifested as the overactivation of ERK1/2 by gene mutations of upstream pathway molecules or regulators and the reactivation of ERK1/2 after inhibition against the above targets. ERK1/2 is a potentially valuable target. In this review, the mechanism of post-translational modification and spatial regulation of ERK1/2 and the application status of corresponding small-molecule inhibitors were discussed. The current antitumor strategy of targeting and regulating ERK1/2 was summarized, and the possibility of exploring potential targets was elucidated, thus providing new insights into the developmental research of ERK1/2 as an ideal anticancer target.