Strong Binding Sites Research Articles

Surface Energy Distribution of Modified Carbon Black and Interfacial Interactions of Filled Rubber Composites.

Carbon black (CB) modification to achieve both homogeneous dispersion and strong interfacial interactions is a challenging subject for high-performance tread rubber composites. The effect of modification on CB surface characteristics is difficult to analyze experimentally, resulting in an uncomprehensive knowledge of the factors influencing interfacial interactions. In this study, 4,4'-diaminodiphenyldisulfide (APDS) was utilized to modify CB. Through molecular simulation techniques, the interfacial binding energy and surface energy distribution were obtained to analyze the interfacial interaction and determine the influence of modifiers on strong binding sites on the CB surface. The strong binding sites were preserved, and the overall interaction was enhanced. The experimental results demonstrated that CB dispersion was evidently improved, and strong interfacial interactions were effectively maintained, verifying the results of molecular simulation. This study elucidated the critical effect of strong binding sites on the CB surface regarding interfacial interactions and also provided theoretical guidance for CB modification. The method of calculating the surface energy distribution of fillers by molecular simulation provides a new efficient strategy for interfacial characterization and modifier evaluation.

Synergistic Binding Sites in a Robust and Scalable Metal-Organic Framework for Record CH4 Capture.

Effectual CH4 reclamation from CH4/N2 blends by existing physisorbents in industrialization confronts the adversity of frustrated separation performance, weak structural strength, and restricted scale-up preparation. To solve aforesaid bottlenecks, herein, a strategy is presented to fabricate synergistic strong recognition binding sites in a robust and scalable optimum Cu(pma)2 with ultramicroporous feature regarding superb CH4 separation versus N2. By virtue of the synergistic contribution of multiple affinities accompanied by enormous potential field overlap of pore restriction, it imparts strong recognition binding toward CH4 molecules. Equilibrium adsorption bears a record KH, CH4 (88.2cm3(STP) g-1bar-1), CH4 uptake (48.5cm3(STP) g-1bar-1), CH4 stacking density (303.9g L-1), separation potential (1.52mol L-1) coexisting with one of the highest CH4/N2 selectivity (11.5) and Q0 st, CH4 (29.8kJ mol-1) hitherto, authorizing a novel benchmark. Thermodynamically driven separation mechanisms within Cu(pma)2-established synergy of strong recognition forces are deciphered by in situ PXRD and FT-IR combined with theoretical studies. The breakthrough effect of the highest CH4 dynamic uptake (28.8cm3(STP) g-1) in cooperation with exceptional recyclability and easy synthesis scalability under ambient conditions strengthened the attractiveness of Cu(pma)2.

Multi-plateau water adsorption of pyrene-based covalent organic frameworks for potential humidity control

Indoor air humidity significantly influences air quality, human health, and work performance. Covalent organic frameworks (COFs) have been proven effective in humidity regulation; however, challenges remain in broadening their range of humidity control. This study designs and synthesizes a series of pyrene-based crystalline COFs as humidity control materials, investigating the moisture adsorption–desorption characteristics under structural modulation. Among these, PY-3,3′-BPY-COF exhibits unique multi-step adsorption isotherms, achieving the highest water uptake capacity (1 g/g) and efficient water uptake-release cycles. Theoretical and experimental analyses reveal a linear relationship between the maximum water uptake rate and the specific surface area, while the adsorption inflection points are influenced by the water binding energy and pore size distribution. Importantly, the introduction of strong binding sites promotes multi-step adsorption phenomena, significantly enhancing the humidity control capabilities of COFs across a wide range of humidity levels. This research introduces an innovative approach for broad-spectrum indoor humidity control and reveals the fundamental relationship between the structure characteristics of COFs and their capabilities in water adsorption and release.

Thermally regulated gating phenomenon in bio-derived ultra-narrow nanoporous carbon for enhancing hydrogen isotope separation

The temperature-triggered gating in flexible nanoporous frameworks exhibits dynamic nanopore regulation under external stimuli, leading to optimum pore sizes and enhanced selectivity for isotopologue separation. In this work, we report one of the very rare observations of temperature-responsive gating in efficient bio-derived ‘nanoporous carbon’ material. The distinctive characteristics of this material, such as its suitable pore sizes for Kinetic Quantum Sieving (KQS) that lead to strong diffusion limitation, as well as its capacity to operate at higher temperatures, overcome the limitations of existing crystalline porous materials. It is remarkable that this activated carbon derived from biological sources, even without any strong binding sites, can release hydrogen isotopologues at a higher temperature of 180 K in comparison to MOF-74(Ni), which possesses many open metal sites but releases mostly at 90–100 K. The separation performance is also demonstrated to reach up to 120 K, and only six separation cycles are needed to enrich from a low concentration of 4 % to –92 % D2 in a mixture of deuterium (D2/H2). This finding suggests that inexpensive porous carbon’s thermal pore size modulation can significantly increase the operating temperature for precise separation of hydrogen isotopologues.

Spectroscopic Response of Chiral Proteophenes Binding to Two Chiral Insulin Amyloids

AbstractWe recently reported on 8 different pentameric oligothiophenes, denoted proteophenes, with different amino acid substitution patterns along the conjugated thiophene backbone. The proteophenes were forming chiral both molecular (solvent dissolved) and self‐assembled nano‐architectonic structures, the latter having approximately 5–6 times greater ICD responses. Herein, two proteophenes, HS‐84‐E−E and HS‐84‐K−K, were further investigated in terms of binding to two chiral variants of insulin amyloid fibrils. Binding curves based on fluorescence revealed strong primary binding sites for both proteophenes and more unspecific secondary binding for especially the latter. Interestingly, their induced circular dichroism (ICD) responses were similar to or stronger than for their solvent form and showed a complicated alteration upon binding suggesting that the microstructure at the binding site governs the helical structure of the ligand. Hyperspectral fluorescence microscopy and FLIM revealed more details on the molecular binding in terms of proteophene emission decay‐times. Vibrational circular dichroism (VCD) analysis showed that VCD signal of amyloid fibrils was enhanced upon binding of proteophenes, suggesting changes in the amyloid microstructures.

Water Sorption on Isoreticular CPO-27-Type MOFs: From Discrete Sorption Sites to Water-Bridge-Mediated Pore Condensation.

Pore engineering is commonly used to alter the properties of metal-organic frameworks. This is achieved by incorporating different linker molecules (L) into the structure, generating isoreticular frameworks. CPO-27, also named MOF-74, is a prototypical material for this approach, offering the potential to modify the size of its one-dimensional pore channels and the hydrophobicity of pore walls using various linker ligands during synthesis. Thermal activation of these materials yields accessible open metal sites (i.e., under-coordinated metal centers) at the pore walls, thus acting as strong primary binding sites for guest molecules, including water. We study the effect of the pore size and linker hydrophobicity within a series of Ni2+-based isoreticular frameworks (i.e., Ni2L, L = dhtp, dhip, dondc, bpp, bpm, tpp), analyzing their water sorption behavior and the water interactions in the confined pore space. For this purpose, we apply water vapor sorption analysis and Fourier transform infrared spectroscopy. In addition, defect degrees of all compounds are determined by thermogravimetric analysis and solution 1H nuclear magnetic resonance spectroscopy. We find that larger defect degrees affect the preferential sorption sites in Ni2dhtp, while no such indication is found for the other materials in our study. Instead, strong evidence is found for the formation of water bridges/chains between coordinating water molecules, as previously observed for hydrophobic porous carbons and mesoporous silica. This suggests similar sorption energies for additional water molecules in materials with larger pore sizes after saturation of the primary binding sites, resulting in more bulk-like water arrangements. Consequently, the sorption mechanism is driven by classical pore condensation through H-bonding anchor sites instead of sorption at discrete sites.

Sodium dodecyl sulfate rearranges the conformation of transferrin and attenuates its iron-binding capacity

Sodium dodecyl sulfate (SDS), an anionic surfactant used in many cleaning and hygiene products, is known for its dermal and respiratory toxicity. However, how this surfactant influences the iron dynamics within the body and the mechanism is unknown. We explored the interaction between SDS and human transferrin (HTF), focusing on the effects on iron-binding capacity and structural changes. Results revealed that SDS exposure led to a significant release of iron from HTF in a dose-dependent manner, changing its structure and reducing the iron-binding ability. Spectroscopic analyses showed that the protein secondary structure and skeleton, as well as the micro-environment of aromatic amino acids of HTF, were destroyed after SDS binding. Isothermal titration calorimetry (ITC) results (ΔG, ΔS, and ΔH were −40.1 kcal·mol−1, 0.16 kcal·mol−1·K-1, and 10.1 kcal·mol−1, respectively) indicated a spontaneous and hydrophobic interaction with one strong binding site. Molecular docking identified the preferred binding sites, emphasizing hydrophobic forces (with the hydrophobic tail) and hydrogen bonds (with the hydrophilic head) as the primary driving forces, which aligns with the ITC results. Overall, this comprehensive analysis sheds light on the intricate interplay between SDS and HTF, providing insights into potential health risks associated with SDS exposure.

Interactions between dissolved organic matter with different molecular weights and nonylphenol in surface water bodies

Dissolved organic matter (DOM) has a complex composition, which can interact with various pollutants and affect the removal of pollutants. Therefore, a thorough understanding of the interaction between the encccvironmental hormone nonylphenol (NP) and DOM is crucial for environmental impact and development. In this study, the interaction was investigated by means of excitation emission matrix (EEM) fluorescence spectroscopy, UV–Vis spectroscopy, FT-IR spectroscopy, nuclear magnetic resonance (NMR) and complex model analysis. The interaction between different MW DOM and NP was verified by the spectral characterization data. According to the characterization analysis, the main components of DOM in water samples were proteinoid (C1, C2, C4) with MW < 1 k Da, and their binding capacity (log Ka value) and binding site number (n) showed the maximum values (3.37, 3.24, 3.26; 0.81, 1.22, 0.52). For the humus like substance (C3) with larger molecular weight, the log Ka value and the number of binding points n increased with increasing molecular weight, and the maximum values were 3.13 and 0.31, respectively. It can be seen that low molecular weight proteins have strong binding ability and binding sites with NP, and high molecular weight humus also have strong binding ability. Overall, the interaction between DOM and NP has molecular weight dependence and heterogeneity. The purpose of this study is to deeply understand the interaction characteristics of different MW DOM with NP, and to provide theoretical support and reference for the study of the removal effects of NP pollutants.

Computational approach for decoding malaria drug targets from single-cell transcriptomics and finding potential drug molecule

Malaria is a deadly disease caused by Plasmodium parasites. While potent drugs are available in the market for malaria treatment, over the years, Plasmodium parasites have successfully developed resistance against many, if not all, front-line drugs. This poses a serious threat to global malaria eradication efforts, and the continued discovery of new drugs is necessary to tackle this debilitating disease. With recent unprecedented progress in machine learning techniques, single-cell transcriptomic in Plasmodium offers a powerful tool for identifying crucial proteins as a drug target and subsequent computational prediction of potential drugs. In this study, We have implemented a mutual-information-based feature reduction algorithm with a classification algorithm to select important proteins from transcriptomic datasets (sexual and asexual stages) for Plasmodium falciparum and then constructed the protein-protein interaction (PPI) networks of the proteins. The analysis of this PPI network revealed key proteins vital for the survival of Plasmodium falciparum. Based on the function and identification of a few strong binding sites on a couple of these key proteins, we computationally predicted a set of potential drug molecules using a deep learning-based technique. Lead drug molecules that satisfy ADMET and drug-likeliness properties are finally reported out of the generated drugs. The study offers a general computational pipeline to identify crucial proteins using scRNA-seq data sets and further development of potential new drugs.

NP-Collabs: Investigating Counterion-Mediated Bridges in the Multiply Phosphorylated Tau-R2 Repeat.

Tau is an intrinsically disordered (IDP) microtubule-associated protein (MAP) that plays a key part in microtubule assembly and organization. The function of tau can be regulated by multiple phosphorylation sites. These post-translational modifications are known to decrease the binding affinity of tau for microtubules, and abnormal tau phosphorylation patterns are involved in Alzheimer's disease. Using all-atom molecular dynamics simulations, we compared the conformational landscapes explored by the tau R2 repeat domain (which comprises a strong tubulin binding site) in its native state and with multiple phosphorylations on the S285, S289, and S293 residues, with four different standard force field (FF)/water model combinations. We find that the different parameters used for the phosphate groups (which can be more or less flexible) in these FFs and the specific interactions between bulk cations and water lead to the formation of a specific type of counterion bridge, termed nP-collab (for nphosphate collaboration, with n being an integer), where counterions form stable structures binding with two or three phosphate groups simultaneously. The resulting effect of nP-collabs on the tau-R2 conformational space differs when using sodium or potassium cations and is likely to impact the peptide overall dynamics and how this MAP interacts with tubulins. We also investigated the effect of phosphoresidue spacing and ionic concentration by modeling polyalanine peptides containing two phosphoserines located one-six residues apart. Three new metrics specifically tailored for IDPs (proteic Menger curvature, local curvature, and local flexibility) were introduced, which allow us to fully characterize the impact of nP-collabs on the dynamics of disordered peptides at the residue level.

Efficient adsorptive separation of nitrotoluene isomers via a stable and low-cost metal–organic framework with descending affinity order of meta-/ortho-/para-isomers

Obtaining purified nitrotoluenes from their mixture is significant but challenging due to their similar molecular sizes and physical properties. To overcome this challenge, here we report a stable, inexpensive and green-synthesized aluminium-based metal–organic framework (MIL-160) to separate the nitrotoluene mixtures. The appropriate pore size and pore environment permitted MIL-160 to exhibit a rare meta-nitrotoluene (m-NT) preference and always maintain the meta- > ortho- > para-nitrotoluene (m- > o- > p-NT) adsorption order in dynamic breakthrough and pulse modes as well as batch-mode adsorption. Theoretical calculations revealed that the abundant H/O atoms in the confined nanospace provided strong binding sites for selectively capturing nitrotoluene isomers. Specifically, due to difference in shape matching, the strongest host–guest interactions occurred in m-NT@MIL-160, followed by o-NT@MIL-160, and last p-NT@MIL-160. Notably, breakthrough experiments confirmed that a variety of binary and ternary mixtures can be separated via continuous adsorption. The dynamic adsorption stage of ternary mixture directly produced 0.33 mmol g−1 of pure p-NT, and the eluent in the desorption stage contained a high content of m-NT. Additional dynamic adsorption model fitting results indicated that the outstanding dynamic separation performance was also achieved from kinetic factors. These results lay the foundation for the effective separation of nitrotoluene mixtures.

CircHIPK3 nucleates IGF2BP2 and functions as a competing endogenous RNA

Circular RNAs represent a class of endogenous RNAs that regulate gene expression and influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Using time-course depletion of circHIPK3 and specific candidate RNA-binding proteins, we identify several perturbed genes by RNA sequencing analyses. Expression-coupled motif analyses identify an 11-mer motif within circHIPK3, which also becomes enriched in genes that are downregulated upon circHIPK3 depletion. By mining eCLIP datasets and combined with RNA immunoprecipitation assays, we demonstrate that the 11-mer motif constitutes a strong binding site for IGF2BP2 in bladder cancer cell lines. Our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2-STAT3 mRNA binding and, thereby, STAT3 mRNA levels. Surprisingly, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Our results support a model where a few cellular circHIPK3 molecules can induce IGF2BP2 condensation, thereby regulating key factors for cell proliferation.

CircHIPK3 nucleates IGF2BP2 and functions as a competing endogenous RNA.

Circular RNAs represent a class of endogenous RNAs that regulate gene expression and influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Using time-course depletion of circHIPK3 and specific candidate RNA-binding proteins, we identify several perturbed genes by RNA sequencing analyses. Expression-coupled motif analyses identify an 11-mer motif within circHIPK3, which also becomes enriched in genes that are downregulated upon circHIPK3 depletion. By mining eCLIP datasets and combined with RNA immunoprecipitation assays, we demonstrate that the 11-mer motif constitutes a strong binding site for IGF2BP2 in bladder cancer cell lines. Our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2-STAT3 mRNA binding and, thereby, STAT3 mRNA levels. Surprisingly, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Our results support a model where a few cellular circHIPK3 molecules can induce IGF2BP2 condensation, thereby regulating key factors for cell proliferation.

Suitable Pore Confinement with Multiple Interactions in a Low-Cost Zeolitic Imidazolate Framework for Efficient Xe Capture and Separation

The increasing industrial demand for the noble gases xenon (Xe) and krypton (Kr), along with growing environmental concerns on their radionuclides, has made the efficient separation and purification of Xe and Kr a critical issue. Leveraging advanced porous materials to achieve highly efficient adsorptive Xe/Kr separation has been recognized as an energy-saving and economical alternative to the widely used cryogenic distillation technology. Herein, we present a stable, low-cost, and easily scalable zeolitic imidazolate framework (ZIF) material, ZIF-4, for effective xenon adsorption and separation. ZIF-4 possesses uniformly distributed pore cavities with ideally matched pore size (4.3 Å) with that of Xe atom (4.047 Å), providing appropriate pore confinement for Xe binding. Sorption isotherms of ZIF-4 demonstrate the remarkably high Xe uptake (1.64 mmol/g at 0.2 bar and 298 K) and excellent Xe/Kr separation selectivity (16.2 for IAST selectivity of 20/80 Xe/Kr gas mixtures). Breakthrough experiments further validate the efficient separation performance of ZIF-4 in both binary Xe/Kr (20/80) gas mixtures and under dilute conditions. Single-crystal X-ray diffraction studies of activated and Xe-loaded ZIF-4 crystals reveal that the flexible pore cavities of ZIF-4 can self-adaptively adsorb and accommodate Xe atoms through the rotation of imidazolate rings, forming multiple Xe···H and Xe···π interactions to create strong binding sites for Xe capture and discrimination. The stability, economic feasibility, and scalability of ZIF-4 underscore its significant potential for industrial Xe/Kr separation.

Increased chromatin accessibility mediated by nuclear factor I drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer.

Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which these variants drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full-length AR (ARfl), despite its continued high-level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in VCaP16 cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression in VCaP cells increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and NFIX knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.

CircHIPK3 nucleates IGF2BP2 and functions as a competing endogenous RNA.

Circular RNAs (circRNAs) represent a class of widespread endogenous RNAs that regulate gene expression and thereby influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Specifically, we use temporal depletion of circHIPK3 or specific RNA binding proteins (RBPs) and identify several perturbed genes by RNA sequencing analyses. Using expression-coupled motif analyses of mRNA expression data from various knockdown experiments, we identify an 11-mer motif within circHIPK3, which is also enriched in genes that become downregulated upon circHIPK3 depletion. By mining eCLIP datasets, we find that the 11-mer motif constitutes a strong binding site for IGF2BP2 and validate this circHIPK3-IGF2BP2 interaction experimentally using RNA-immunoprecipitation and competition assays in bladder cancer cell lines. Our results suggest that circHIPK3 and IGF2BP2 mRNA targets compete for binding. Since the identified 11-mer motif found in circHIPK3 is enriched in upregulated genes following IGF2BP2 knockdown, and since IGF2BP2 depletion conversely globally antagonizes the effect of circHIPK3 knockdown on target genes, our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2- STAT3 mRNA binding and thereby STAT3 mRNA levels. However, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Finally, we show that circHIPK3 expression correlates with overall survival of patients with bladder cancer. Our results are consistent with a model where relatively few cellular circHIPK3 molecules function as inducers of IGF2BP2 condensation thereby regulating STAT3 and other key factors for cell proliferation and potentially cancer progression.

Hydroxyl-functionalized linker endows an ultra-microporous aluminum based metal–organic framework with electronegative site for enhancing ethane/ethylene separation

Efficient purification of ethylene (C2H4) from the cracking gas containing a small amount of ethane (C2H6) by selective adsorption of C2H6 is meaningful but remains challenging. Aluminum-based metal–organic frameworks (Al-MOFs) with ultra-microporous structure show preferential adsorption of C2H6 over C2H4, relying on the existence of multiple hydrogen bonding acceptors (e.g., AlO6 polyhedra) for C2H6 molecule in the confined pores. However, most Al-MOFs exhibit limited C2H6/C2H4 selectivity (<2), which lack other strong preferential binding sites for C2H6. Here we report that a hydroxyl functionalized Al-MOF (i.e., CAU-1-OH) exhibits notably improved C2H6/C2H4 selectivity (2.13) and C2H6 uptake (3.95 mmol g−1) at 298 K and 1 bar compared to its amino-functionalized counterpart, CAU-1-NH2. Prior to experiment, theoretical calculations were performed, revealing that O atom from hydroxyl group in CAU-1-OH acts as a fairly strong hydrogen bond acceptor due to its more negative charge than N atom in CAU-1-NH2. The in-situ infrared experiment further confirmed the formation of multiple hydrogen bonds (C–H⋅⋅⋅O) between CAU-1-OH and C2H6 molecules, which plays vital role for C2H6-selective capture. The actual potential for C2H4 purification was fully demonstrated by dynamic breakthrough experiments, in which CAU-1-OH displayed excellent separative performance from C2H6/C2H4 (1/15, v/v) mixture. Moreover, the structural stability and excellent recyclability suggested and the promise for cost-effective industrial application in C2H6/C2H4 separation.

Influence of carbon black surface characteristics on CB-NR interfacial interaction: Molecular simulation and experimental study

Carbon black (CB) is the most widely used reinforcing filler in rubber industry, but the effects of CB surface characteristics on interfacial interaction of CB-filled rubber composites are still not fully described. Combined the experimental and molecular simulation techniques, the aim of this study is to individually investigate the influence of various CB surface characteristics, such as surface area, surface crystallite size, roughness and surface energy, on CB-natural rubber (NR) interfacial interaction to obtain a deep interpretation on the properties of rubber composites. Experimental results showed that the specific surface area is the primary factor affecting overall CB-NR interaction, followed by filler network. Meanwhile, CB surface model with different roughness based on experimental parameters were constructed, and the simulation results revealed that CB-NR interfacial interaction mainly occurred at the interface 2–3 nm. The binding energy distribution on CB surface was analyzed, and rough region is weaker than crystal region and amorphous region. The strongest binding sites are located at the junction of rough region and amorphous region. The results in this study are expected to provide a theoretic guide for optimizing the CB characteristics and developing new rubber-grade CB.

Identification of Electrostatic Hotspots at the Binding Interface of Amylin and InsulinDegrading Enzyme: A Structural and Biophysical Investigation

Amylin, also known as islet amyloid polypeptide (IAPP), is a metabolic homeostasis-related hormone that is produced and released by the β cells of the pancreas, the same cells that produce insulin. Insulin-degrading enzyme (IDE) is a protease enzyme that plays an essential role in the breakdown and degradation of various peptides, including insulin and amylin. Direct binding &amp; interaction between amylin and IDE is inextricably linked to the degradation of amylin, and research and development effort in this area is crucial to understand the potential therapeutic implications of disrupting the IDE-amylin interaction in the context of conditions where metabolic homeostasis needs to be regulated, such as diabetes and obesity. Here, this article incorporates currently available experimental complex structure of amylin and IDE, and delves deep into the interstructural biophysics underlying the binding interface of the two interacting partners. With a set of comprehensive structural biophysical analysis, this article identified an intriguing region of high electrostatic potential indicative of strong binding sites between the first N-terminal lysine (Lys1, K1) residue of amylin and Glu341 (E341) of IDE. This unique electrostatic hotspot presented herein paves the way for the rational design of drug-like small molecules that can selectively disrupt this interaction, offering a targeted therapeutic strategy for improved metabolic homeostasis, particularly for patients with diabetes and obesity.

DNA fragility at topologically associated domain boundaries is promoted by alternative DNA secondary structure and topoisomerase II activity.

CCCTC-binding factor (CTCF) binding sites are hotspots of genome instability. Although many factors have been associated with CTCF binding site fragility, no study has integrated all fragility-related factors to understand the mechanism(s) of how they work together. Using an unbiased, genome-wide approach, we found that DNA double-strand breaks (DSBs) are enriched at strong, but not weak, CTCF binding sites in five human cell types. Energetically favorable alternative DNA secondary structures underlie strong CTCF binding sites. These structures coincided with the location of topoisomerase II (TOP2) cleavage complex, suggesting that DNA secondary structure acts as a recognition sequence for TOP2 binding and cleavage at CTCF binding sites. Furthermore, CTCF knockdown significantly increased DSBs at strong CTCF binding sites and at CTCF sites that are located at topologically associated domain (TAD) boundaries. TAD boundary-associated CTCF sites that lost CTCF upon knockdown displayed increased DSBs when compared to the gained sites, and those lost sites are overrepresented with G-quadruplexes, suggesting that the structures act as boundary insulators in the absence of CTCF, and contribute to increased DSBs. These results model how alternative DNA secondary structures facilitate recruitment of TOP2 to CTCF binding sites, providing mechanistic insight into DNA fragility at CTCF binding sites.