Mode Of Dimerization Research Articles

On the nature of hydrogen bonding in the H2S dimer.

Hydrogen bonding is a central concept in chemistry and biochemistry, and so it continues to attract intense study. Here, we examine hydrogen bonding in the H2S dimer, in comparison with the well-studied water dimer, in unprecedented detail. We record a mass-selected IR spectrum of the H2S dimer in superfluid helium nanodroplets. We are able to resolve a rotational substructure in each of the three distinct bands and, based on it, assign these to vibration-rotation-tunneling transitions of a single intramolecular vibration. With the use of high-level potential and dipole-moment surfaces we compute the vibration-rotation-tunneling dynamics and far-infrared spectrum with rigorous quantum methods. Intramolecular mode Vibrational Self-Consistent-Field and Configuration-Interaction calculations provide the frequencies and intensities of the four SH-stretch modes, with a focus on the most intense, the donor bound SH mode which yields the experimentally observed bands. We show that the intermolecular modes in the H2S dimer are substantially more delocalized and more strongly mixed than in the water dimer. The less directional nature of the hydrogen bonding can be quantified in terms of weaker electrostatic and more important dispersion interactions. The present study reconciles all previous spectroscopic data, and serves as a sensitive test for the potential and dipole-moment surfaces.

The crystal structure of Nictaba reveals its carbohydrate-binding properties and a new lectin dimerization mode.

Nictaba is a (GlcNAc)n-binding, stress-inducible lectin from Nicotiana tabacum that serves as a representative for the Nictaba-related lectins, a group of proteins that play pivotal roles in plant defense mechanisms and stress response pathways. Despite extensive research into biological activities and physiological role(s) of the lectin, the three-dimensional structure of Nictaba remained largely unknown. Here, we report crystal structures for Nictaba in the apo form and bound to chitotriose. The structures reveal that the Nictaba protomer has a jelly-roll fold, similar to the cucumber lectin Cus17, but exhibit a unique and previously unseen mode of dimerization. The chitotriose binding mode, similar to Cus17, centers around the central GlcNAc residue, providing insights into the determinants of specificity of Nictaba towards carbohydrate structures. By integrating these structural insights with inputs from glycan arrays, molecular docking, and molecular dynamics simulations, we propose that Nictaba employs a single carbohydrate-recognition domain within each of the two subunits in the dimer to display pronounced specificity towards GlcNAc-containing carbohydrates. Furthermore, we identified amino acid residues involved in the extended binding site capable of accommodating structurally diverse high-mannose and complex N-glycans. Glycan array and in silico analyses revealed interactions centered around the conserved Man3GlcNAc2 core, explaining the broad recognition of N-glycan structures. Collectively, the structural and biochemical insights presented here fill a void into the atlas of lectin structure-function relationships and pave the way for future developments in plant stress biology and lectin-based applications.

Cross-Coupling of NHC/CAAC-Based Carbodicarbene: Synthesis of Electron-Deficient Diradicaloids.

Herein, we report nickel(0)-catalyzed cross-coupling reactions of NHC/CAAC-based carbodicarbene (NHC = N-heterocyclic carbene and CAAC = cyclic(alkyl)(amino)carbene) with different aryl chlorides, bromides, and iodides. The resulting aryl-substituted cationic carbodicarbene derivatives are prone to one-electron oxidation yielding radical-dications, which, depending on the aryl motif employed, follow different modes of radical-radical dimerization and constitute an entry point to carbon/nitrogen- and nitrogen/nitrogen-centered diradicaloids. Subsequently, this coupling strategy was strategically applied to the synthesis of p-phenylene- and p,p'-biphenylene-bridged carbon/carbon-centered electron-deficient diradicaloids. The employed π-conjugated spacer plays a crucial role in determining the triplet population at room temperature by modulation of the singlet-triplet gap: EPR inactive for p-phenylene vs EPR active for p,p'-biphenylene. Nearly two decades after the disclosure of carbodicarbenes as donor-stabilized atomic carbon equivalents by Tonner and Frenking in 2007, we demonstrate their cross-couplings with a series of aryl halides/dihalides and, based on this, developed a modular methodology for the systematic synthesis of various electron-deficient diradicaloids.

New Hypothesis on Enhancing β-Sheet Formation during the Tau Fragment Dimer Transition from a Flexible Monomer: Insights into Primary Nucleation Processes by Histidine Behaviors.

Slight perturbations in pH can have significant effects on the primary nucleation processes of the tau protein. The behaviors of histidine due to its pivotal role in modulating H-bonding network interactions and electrostatic interactions have garnered considerable attention, as it can influence the structural characteristics and aggregation properties. However, the nucleation mechanisms and related intermediates are still unclear. In the current study, we performed nine independent replica exchange molecular dynamics simulations to investigate dimer formation involving R3(εδ) in conjunction with the R1, R2, and R4 monomers. Our findings substantiate that, in comparison to R1-R3(εδ) and R4-R3(εδ) systems, the R2-R3(εδ) systems consistently manifest the highest averaged β-sheet content, with the fundamental feature of R3(εδ) promoting R2 rearrangement. Our comprehensive analysis reveals that high-β-sheet-rich systems exhibit a conserved three/five β-strand structure. In these β-strand-rich systems, one chain [R1/R2/R4 or R3(εδ)] with robust intrachain H-bonding interactions coordinates with another chain through interchain H-bonding interactions, contributing to the overall stability. Furthermore, we discuss distinct histidine behaviors, including backbone/side chain interactions and donor/acceptor roles. This study provides a comprehensive understanding of the aggregation propensities of soluble tau oligomers and sheds light on the primary nucleation mechanism. It contributes to a new perspective for understanding protein folding and misfolding.

Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases.

The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R) are homodimeric transmembrane glycoproteins that transduce signals across the membrane on binding of extracellular peptide ligands. The structures of IR/IGF1R fragments in apo and liganded states have revealed that the extracellular subunits of these receptors adopt Λ-shaped configurations to which are connected the intracellular tyrosine kinase (TK) domains. The binding of peptide ligands induces structural transitions in the extracellular subunits leading to potential dimerization of transmembrane domains (TMDs) and autophosphorylation in TKs. However, the activation mechanisms of IR/IGF1R, especially the role of TMDs in coordinating signal-inducing structural transitions, remain poorly understood, in part due to the lack of structures of full-length receptors in apo or liganded states. While atomistic simulations of IR/IGF1R TMDs showed that these domains can dimerize in single component membranes, spontaneous unbiased dimerization in a plasma membrane having a physiologically representative lipid composition has not been observed. We address this limitation by employing coarse-grained (CG) molecular dynamics simulations to probe the dimerization propensity of IR/IGF1R TMDs. We observed that TMDs in both receptors spontaneously dimerized independent of their initial orientations in their dissociated states, signifying their natural propensity for dimerization. In the dimeric state, IR TMDs predominantly adopted X-shaped configurations with asymmetric helical packing and significant tilt relative to the membrane normal, while IGF1R TMDs adopted symmetric V-shaped or parallel configurations with either no tilt or a small tilt relative to the membrane normal. Our results suggest that IR/IGF1R TMDs spontaneously dimerize and adopt distinct dimerized configurations.

High-Performance Multicolor Organic Light-Emitting Diodes Based on a Pt(II) Carbene Complex Featuring Hemiligand Interaction.

Utilizing a single organic light-emitting diode (OLED) architecture for multicolor emissions can significantly simplify manufacturing progress and broaden applications. Here, we report on a carbene-based Pt(II) complex, designated as Pt(pyiOppy), which exhibits an unusual dimeric packing mode solely by hemiligand π···π stacking. This feature is distinct from the well-known Pt···Pt or Pt···ligand interactions. The dimer persists in new types of orbital combinations, along with its triplet transition state, which are evidenced for the first time. Pt(pyiOppy), under various doping concentrations in a solid matrix, demonstrates multicolor emissions ranging from green to red, all exhibiting high photoluminescent quantum efficiencies (48-97%). The devices incorporating Pt(pyiOppy) can emit green, yellow, orange, and red lights, covering a CIE coordinate range of (0.28-0.65, 0.61-0.34). All the devices also achieve appreciable maximum external quantum efficiencies (9.4-17.2%) and impressive lifetimes of hundreds of hours (LT70 at 1000 cd/m2). These findings showcase a new type of Pt(II) aggregate enabling well-controlled, multicolor high-performance phosphorescent OLEDs.

5119 Structural basis for glucocorticoid receptor multimerization

Abstract Disclosure: E. Estébanez-Perpiñá: None. Abstract ENDO-2024 - BostonStructural basis for glucocorticoid receptor multimerization Andrea Alegre-Martí[1]*, Alba Jimenez-Panizo2*, Agustina Lafuente3, Montserrat Abella[1], Thomas A Johnson2, Paloma Pérez4, Juan Fernández-Recio5, Diego M. Presman3, Gordon L. Hager2, Pablo Fuentes-Prior[1], Eva Estébanez-Perpiñá[1] [1]Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain.2National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA.3IFIBYNE, UBA-CONICET, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, C1428EGA, Argentina.4Instituto de Biomedicina de Valencia (IBV)-CSIC, 46010, Valencia, Spain.5Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC - Universidad de La Rioja - Gobierno de La Rioja, 26007 Logroño, Spain. Abstract: The glucocorticoid receptor (GR) is a ubiquitously e2xpressed ligand-regulated transcription factor essential for life and one of the most targeted proteins in drug discovery due to its powerful anti-inflammatory actions. The functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity in cells, remains disputed. Here we present a new crystal structure of agonist-bound ancient GR-LBD in a large cell, along with a thorough analysis of previous structural work. The building block of the current structure is a homodimer we previously identified in GR-LBD crystals and its biological relevance has been verified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in live cells. Several mutually exclusive multimeric assemblies of this dimer in the crystal highlight the versatility of GR-LBD for self-association and reveal implications for the conformation of the active full-length receptor. Our results underscore the relevance of non-canonical dimerization modes for GR-LBD, especially of contacts made by key residues such as Tyr545, Pro637 and Asp641. Of note, a non-conservative mutation of the latter, p.Asp641Val, causes Chrousos syndrome in humans. Understanding relevant quaternary assemblies of the GR is pivotal not only to understand and predict the therapeutic outcome of major blockbuster drugs but also to lessen their deleterious side effects and open new avenues for drug design. Presentation: 6/3/2024

Cryo-EM structure of human class C orphan GPCR GPR179 involved in visual processing

GPR179, an orphan class C GPCR, is expressed at the dendritic tips of ON-bipolar cells in the retina. It plays a pivotal role in the initial synaptic transmission of visual signals from photoreceptors, and its deficiency is known to be the cause of complete congenital stationary night blindness. Here, we present the cryo-electron microscopy structure of human GPR179. Notably, the transmembrane domain (TMD) of GPR179 forms a homodimer through the TM1/7 interface with a single inter-protomer disulfide bond, adopting a noncanonical dimerization mode. Furthermore, the TMD dimer exhibits architecture well-suited for the highly curved membrane of the dendritic tip and distinct from the flat membrane arrangement observed in other class C GPCR dimers. Our structure reveals unique structural features of GPR179 TMD, setting it apart from other class C GPCRs. These findings provide a foundation for understanding signal transduction through GPR179 in visual processing and offers insights into the underlying causes of ocular diseases.

Heterochromatin protein 1 alpha (HP1α) undergoes a monomer to dimer transition that opens and compacts live cell genome architecture.

Our understanding of heterochromatin nanostructure and its capacity to mediate gene silencing in a living cell has been prevented by the diffraction limit of optical microscopy. Thus, here to overcome this technical hurdle, and directly measure the nucleosome arrangement that underpins this dense chromatin state, we coupled fluorescence lifetime imaging microscopy (FLIM) of Förster resonance energy transfer (FRET) between histones core to the nucleosome, with molecular editing of heterochromatin protein 1 alpha (HP1α). Intriguingly, this super-resolved readout of nanoscale chromatin structure, alongside fluorescence fluctuation spectroscopy (FFS) and FLIM-FRET analysis of HP1α protein-protein interaction, revealed nucleosome arrangement to be differentially regulated by HP1α oligomeric state. Specifically, we found HP1α monomers to impart a previously undescribed global nucleosome spacing throughout genome architecture that is mediated by trimethylation on lysine 9 of histone H3 (H3K9me3) and locally reduced upon HP1α dimerisation. Collectively, these results demonstrate HP1α to impart a dual action on chromatin that increases the dynamic range of nucleosome proximity. We anticipate that this finding will have important implications for our understanding of how live cell heterochromatin structure regulates genome function.

Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases.

The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R) are homodimeric transmembrane glycoproteins that transduce signals across the membrane on binding of extracellular peptide ligands. The structures of IR/IGF1R fragments in apo and liganded states have revealed that the extracellular subunits of these receptors adopt Λ-shaped configurations to which are connected the intracellular tyrosine kinase (TK) domains. The binding of peptide ligands induces structural transitions in the extracellular subunits leading to potential dimerization of transmembrane domains (TMDs) and autophosphorylation in TKs. However, the activation mechanisms of IR/IGF1R, especially the role of TMDs in coordinating signal-inducing structural transitions, remain poorly understood, in part due to the lack of structures of full-length receptors in apo or liganded states. While atomistic simulations of IR/IGF1R TMDs showed that these domains can dimerize in single component membranes, spontaneous unbiased dimerization in a plasma membrane having physiologically representative lipid composition has not been observed. We address this limitation by employing coarse-grained (CG) molecular dynamics simulations to probe the dimerization propensity of IR/IGF1R TMDs. We observed that TMDs in both receptors spontaneously dimerized independent of their initial orientations in their dissociated states, signifying their natural propensity for dimerization. In the dimeric state, IR TMDs predominantly adopted X-shaped configurations with asymmetric helical packing and significant tilt relative to the membrane normal, while IGF1R TMDs adopted symmetric V-shaped or parallel configurations with either no tilt or a small tilt relative to the membrane normal. Our results suggest that IR/IGF1R TMDs spontaneously dimerize and adopt distinct dimerized configurations.

Effector Binding Sequentially Alters KRAS Dimerization on the Membrane: New Insights Into RAS-Mediated RAF Activation.

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.

All-Optical Control of Ultrafast Switching between the Hybridized Plasmonic Fields of Au Nanorod Dimer in fs-nm Scale with Dispersed Femtosecond Laser.

With the increasing demand for ultrafast communication and information processing in future optical chips, arbitrary manipulation of electromagnetic fields in the femtosecond-nanometer spatiotemporal scale has attracted great attention in integrated optics. Manipulation of the nanoscale light field in the real femtosecond temporal domain is challenging work. Here, we have demonstrated all-optical control of ultrafast switching between the hybridized plasmonic fields of a Au nanorod dimer in the fs-nm scale using a dispersed femtosecond laser and revealed the transformation process with ultrahigh spatiotemporal resolved technology via the combination of a pump-probe technique and photoemission electron microscopy (PEEM). The results show that we can actively and coherently control the transformation sequence and time (with the shortest temporal interval of around 15 fs) of the two hybridized modes in the Au nanorod dimer by tuning the dispersion of the laser pulse. The nanoscale light manipulation achieved by all-optical control may contribute to the design of high-speed miniaturized signal-processing systems.

Exploring the Diverse Landscape of Fungal Cytochrome P450-Catalyzed Regio- and Stereoselective Dimerization of Diketopiperazines.

Dimeric indole-containing diketopiperazines (di-DKPs) are a diverse group of natural products produced through cytochrome P450-catalyzed C-C or C-N coupling reactions. The regio- and stereoselectivity of these reactions plays a significant role in the structural diversity of di-DKPs. Despite their pivotal role, the mechanisms governing the selectivity in fungi are not fully understood. Employing bioinformatics analysis and heterologous expression experiments, five undescribed P450enzymes (AmiP450, AcrP450, AtP450, AcP450, and AtuP450) responsible for the regio- and stereoselective dimerization of diketopiperazines (DKPs) in fungi are identified. The function of these P450s is consistent with phylogenetic analysis, highlighting their dominant role in controlling the dimerization modes. Combinatorial biosynthesis-based pathway reconstitution of non-native gene clusters expands the chemical space of fungal di-DKPs and reveals that the regioselectivity is influenced by the substrate. Furthermore, multiple sequence alignment and molecular docking of these enzymes demonstrate a C-terminal variable region near the substrate tunnel entrance in AtuP450 that is crucial for its regioselectivity. These findings not only reveal the secret of fungal di-DKPs diversity but also deepen understanding of the mechanisms and catalytic specificity involved in P450-catalyzed dimerization reactions.

Abstract 5782: Probing monomer - dimer and conformational transitions of PLK1 using catalytic and polo-box domain inhibitors

Abstract Polo Like Kinase 1 (PLK1), a sought-after target for drug discovery, is an essential mitotic kinase consisting of a catalytic domain (KD) and a polobox domain (PBD), the latter of which plays roles in substrate recognition, subcellular localization and further acting as an autoinhibitory regulatory domain. PLK1 can exist either in an inhibited closed conformation or an open active state allowing interaction with and phosphorylation of substrates. PLK1 has also been shown to be regulated by interchange between monomeric and dimeric forms through binding to the Bora protein and by activation loop phosphorylation. We have described PBD-binding molecules termed abbapolins that inhibit cellular phosphorylation of a PLK1 substrate and induce loss of intracellular PLK1. In addition, due to their engagement of the cryptic pocket (ligand induced) of the PBD, we proposed that abbapolins would interfere with formation of PLK1 dimers. Here we provide evidence further supporting the ability of abbapolins to block PLK1 cellular dimerization and that this is related to their mechanism of anti-proliferative activity. In a separate study, using a cellular thermal shift assay, KD inhibitors were shown to decrease soluble PLK1, indicating that catalytic-site binding results in less stable PLK1 suggestive of an open conformation. We have extended these observations using a sensitive readout of cellular target engagement employing a Microtag overexpressed PLK1. In this format, we observe heat-induced destabilization of PLK1 upon nanomolar engagement by two lead KD inhibitors, BI2536 and onvansertib, currently being clinically evaluated. Furthermore, cyclapolin 9, a low molecular weight kinase inhibitor that, unlike the other two KD inhibitors does not protrude from the active site, did not induce significant destabilization. We have also carried out experiments using a fluorescently labeled version of BI2536 to probe the conformational effects of PBD binding upon the KD. These data solidify the observations that relief of autoinhibited PLK1 is induced by certain KD binders and highlight the conformational perturbations from KD versus PBD binding. These observations have implications for the development of ATP-competitive PLK1 inhibitors because catalytic inhibitors may conversely promote PLK1 non-catalytic functions, which may explain their lack of clinical efficacy to date. Furthermore, the demonstration that the abbapolins are mechanistically unique in terms of blocking the dimerization of PLK through the PBD provides impetus for their development as next generation PLK1 inhibitors. Citation Format: Mourad Sanhaji, Monika Raab, George Merhej, Chintada Nageswara Rao, Ivan Babic, Elmar Nurmemmedov, Klaus Strebhardt, MIchael Wyatt, Campbell McInnes. Probing monomer - dimer and conformational transitions of PLK1 using catalytic and polo-box domain inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5782.

Destabilization of spin-Peierls phase via a charge-spin modulated Floquet state induced by intramolecular vibrational excitation

The electronic state control using a periodic light field is one of the central subjects in photophysics. In molecular solids, intramolecular vibrations sometimes couple to intermolecular electron transfer, thus modulating electron and spin densities of each molecule. Here, we show that in a quasi-one-dimensional molecular solid K-tetracyanoquinodimethane (TCNQ) in which TCNQ molecules are dimerized by the spin-Peierls mechanism, an intramolecular vibrational excitation with a phase-locked mid-infrared pulse induces a charge-spin modulated Floquet state, which destabilizes the spin-Peierls phase. By detecting reflectivity changes of the intramolecular transition band along the mid-infrared electric field with 6.6-fs probe pulses, we detected high-frequency oscillations reflecting electron- and spin-density modulations synchronized with intramolecular vibrations. More significantly, we observed an oscillation of ~110 cm−1 due to a dimeric mode driven by a decrease in spin-Peierls dimerization. This dimerization reduction was confirmed by measuring transient reflectivity changes of the Mott-gap transition band. These results demonstrate the effectiveness of intramolecular vibrational excitation as a method for Floquet engineering in molecular solids.

Strong anapole-plasmon coupling in dielectric-metallic hybrid nanostructures.

The nanoscale ampification of light-matter interactions exhibits profound potential in multiple scientific fields, such as physics, chemistry, surface science, materials science, and nanophotonics. Nonetheless, achieving robust optical mode coupling within cavities faces significant hurdles due to modal dispersion and weak optical field confinement. In this theoretical investigation, we demonstrate the viability of strong coupling between the anapole mode of a slotted silicon nanodisk and the plasmonic modes of an Ag nanodisk dimer at visible light frequencies. By introducing anapole modes, we successfully confine light to subwavelength volumes, suppressing radiative losses and achieving a remarkable Rabi splitting of 468 meV. This substantial coupling is facilitated by the large spatial overlap of intense optical fields. Capitalizing on this strong mode coupling, we generate novel hybrid energy states with significant electromagnetic field enhancement. Our study serves as a valuable blueprint for designing platforms based on strong anapole mode coupling at visible frequencies and paves the way for deeper explorations into nanoscale light-matter interactions.

Metastability of π-π stacking between the closed-shell ions of like charges

Planar cations or anions can form stacks in crystals or solutions, where the surrounding or environment plays a decisive role as demonstrated in previous studies. However, it remains unclear whether these counterintuitive interactions possess any inherent stability or are thoroughly repulsive if the constraint of environment is removed. In this work, we explored the inherent stability of π-π stacking between closed-shell ions of like charges with prototypes derived from experimental studies. The inherent metastability was identified by the characteristic local minima and the transition states preventing their dissociation and verified by ab initio molecular dynamics (AIMD) simulations. The nature of involved interactions was deciphered with the energy decomposition approach based on the block-localized wavefunction method (BLW-ED). Like the conventional neutral π-π stacking interactions, electron correlation is the most attractive energy component. But it is overturned by the Coulombic repulsion between net charges for all modes of dimerization, resulting in the overall repulsive inter-cation or anion interactions. Contributions from van der Waals interactions were also observed in the reduced density gradient analysis. The origin of the metastability was elucidated by examining the contributions of individual physical factors to the well-depths. The inherent metastability originates from the electron correlation, which dramatically increases due to the enhanced overlap between ions from a transition state to its corresponding minimum.

Simple Air-Stable [3]Radialene Anion Radicals as Environmentally Switchable Catholytes in Water.

The hexacyano[3]radialene radical anion (1) is an attractive catholyte material for use in redox flow battery (RFB) applications. The substitution of cyano groups with ester moieties enhances solubility while maintaining redox reversibility and favorable redox potentials. Here we show that these ester-functionalized, hexasubstituted [3]radialene radical anions dimerize reversibly in water. The dimerization mode is dependent on the substitution pattern and can be switched in solution. Stimuli-responsive behavior is achieved by exploiting an unprecedented tristate switching mechanism, wherein the radical can be toggled between the free radical, a π-dimer, and a σ-dimer-each with dramatically different optical, magnetic, and redox properties-by changing the solvent environment, temperature, or salinity. The symmetric, triester-tricyano[3]radialene (3) forms a solvent-responsive, σ-dimer in water that converts to the radical anion with the addition of organic solvents or to a π-dimer in brine solutions. Diester-tetracyano[3]radialene (2) exists primarily as a π-dimer in aqueous solutions and a radical anion in organic solvents. The dimerization behavior of both 2 and 3 is temperature dependent in methanol solutions. Dimerization equilibrium has a direct impact on catholyte stability during galvanostatic charge-discharge cycling in static H-cells. Specifically, conditions that favor the free radical anion or π-dimer exhibit significantly enhanced cycling profiles.

Integrative modeling of guanylate binding protein dimers.

Guanylate-binding proteins (GBPs) are essential interferon-γ-activated large GTPases that play a crucial role in host defense against intracellular bacteria and parasites. While their protective functions rely on protein polymerization, our understanding of the structural intricacies of these multimerized states remains limited. To bridge this knowledge gap, we present dimer models for human GBP1 (hGBP1) and murine GBP2 and 7 (mGBP2 and mGBP7) using an integrative approach, incorporating the crystal structure of hGBP1's GTPase domain dimer, crosslinking mass spectrometry, small-angle X-ray scattering, protein-protein docking, and molecular dynamics simulations. Our investigation begins by comparing the protein dynamics of hGBP1, mGBP2, and mGBP7. We observe that the M/E domain in all three proteins exhibits significant mobility and hinge motion, with mGBP7 displaying a slightly less pronounced motion but greater flexibility in its GTPase domain. These dynamic distinctions can be attributed to variations in the sequences of mGBP7 and hGBP1/mGBP2, resulting in different dimerization modes. Unlike hGBP1 and its close ortholog mGBP2, which exclusively dimerize through their GTPase domains, we find that mGBP7 exhibits three equally probable alternative dimer structures. The GTPase domain of mGBP7 is only partially involved in its dimerization, primarily due to an accumulation of negative charge, allowing mGBP7 to dimerize independently of GTP. Instead, mGBP7 exhibits a strong tendency to dimerize in an antiparallel arrangement across its stalks. The results of this work go beyond the sequence-structure-function relationship, as the sequence differences in mGBP7 and mGBP2/hGBP1 do not lead to different structures, but to different protein dynamics and dimerization. The distinct GBP dimer structures are expected to encode specific functions crucial for disrupting pathogen membranes.

Chloride-Induced Monomer to Dimer Transition Controls WNK1 Scaffold Activity

Chloride-Induced Monomer to Dimer Transition Controls WNK1 Scaffold Activity