Conformational Stability Research Articles

Corannulene‐Based Quintuple [6]/[7]Helicenes: Well‐Preserved Bowl Core, Inhibited Bowl Inversion and Supramolecular Assembly with Fullerenes

AbstractHerein, corannulene‐based quintuple [6]helicenes (Q[6]H‐1 and Q[6]H‐2) and [7]helicene (Q[7]H) were synthesized via penta‐fold Heck and Mallory reaction. Notably, Q[7]H represents the highest reported helicene based on corannulene. X‐ray crystallography reveals that Q[6]H‐2 adopts a propeller‐shaped conformation with a well‐preserved corannulene core, while Q[6]H‐1 and Q[7]H exhibit quasi‐propeller‐shaped conformations. Upon heating, conformer Q[6]H‐1 undergoes conversion to the thermodynamically more stable conformer Q[6]H‐2, whereas conformer Q[7]H remains unchanged due to larger steric congestion. Racemization of the enantiomer of Q[6]H‐1 and conformational conversion were observed simultaneously at elevated temperature, with DFT studies indicating a racemization barrier of 32.06 kcal ⋅ mol−1. In contrast, the racemization barrier for Q[6]H‐2 was calculated to be 45.46 kcal ⋅ mol−1, indicating exceptional chiral stability. Surprisingly, the bowl inversions of Q[6]H‐1 and Q[6]H‐2 conformers are somewhat inhibited by the helical blades, whereas this was not observed for other possible conformers of Q[6]H. These results first demonstrated that subtle conformational variations can lead to significant changes in chiral stability and bowl inversions of multiple helicenes. Due to the well‐preserved corannulene core, propeller‐shaped conformation and electron complementarity, Q[6]H‐2 can recognize fullerenes in both solution and solid state, which is a rare instance of co‐crystallization assembly between multiple helicenes and fullerenes.

Bioinformatics combined with network pharmacology and experimental validation to identify key biomarkers of hepatocellular carcinoma and corresponding compounds in Radix Astragali and Pueraria Mirifica.

The occurrence and death rates of primary hepatocellular carcinoma (HCC) are increasing, and there remains a shortage of effective oral medications with minimal side effects. We aim to identify potential biomarkers and compounds from Radix Astragali (RA) and Pueraria Mirifica (PM) to treat liver cancer and improve prognosis. Differentially expressed genes (DEGs) associated with HCC were identified by bioinformatics analysis of three datasets, GSE112791, GSE101685, and GSE45114. Using public databases to predict the bioactive components and possible targets of RA and PM. Target crossover from Gene Expression Omnibus (GEO) and public databases were used to identify potential biomarkers for HCC. Subsequently, validation and prognostic value analyses were performed using the Gene Expression Profile Interaction Analysis (GEPIA) platform. The Cytoscape software created a network of "compound targets" to pinpoint compounds linked to the biomarkers. Molecular docking techniques were utilized to validate the connection between these compounds and the identified biomarkers. Ultimately, the HepG2 liver cancer cell line was chosen to assess the inhibitory effect of Hederagenin (HDG) and to confirm the expression of ADH1B through Western blot analysis. In this study, four key biomarkers (NR1I2, ADH1B, NQO1, GHR) were identified. Molecular docking showed that these four core targets could form stable conformations with the corresponding compounds. As the drug concentration decreases, the inhibitory effect on HepG2 diminishes, and the survival rate of HepG2 cells significantly declines following the administration of 100 µmol/L HDG. Compared to the control, the expression of ADH1B protein is significantly increased in HepG2 cells treated with 100 µmol/L HDG. The study identified four key biomarkers (ADH1B, GHR, NQO1, NR1I2) that have prognostic ability for HCC. This study provides biomarkers and potential targeted monomeric medicines for treating HCC.

Identification of Potential Inhibitors of Histone Deacetylase 6 Through Virtual Screening and Molecular Dynamics Simulation Approach: Implications in Neurodegenerative Diseases

Background: Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. Methods: This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. Results: The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein–ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6–ligand complexes, confirming the stability of their interactions. Conclusions: The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.

Elucidating the pathobiology of Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS) with its expanded RNA structure formation and proteinopathy.

Numerous neurological disorders are linked to sequences rich in guanine repeats found in introns, exons, and regulatory regions of genes. These sequences have been observed to form stable G-quadruplex (GQ) structures bothin vitroand in vitro.Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), a slowly progressive neurodegenerative disorder, is associated with the biallelic expansion of (AAGGG)n pathogenic repeats in the second intron of the RFC1 gene. Though these G-rich pathogenic repeats in other neurological diseases are associated with protein loss of function, RNA gain of function, and/or protein gain of function, not much is known about the pathological mechanism associated with CANVAS. Herein, we report the formation of stable GQ conformations in the CANVAS-associated repeats i.e., r(AAGGG)n, where 'r' stands for RNA. These GQs are critical regulators in neurological disorders leading to RNA foci formation and RNA binding protein sequestration. They also alter other causative processes like intron retention, which leads us to hypothesize a toxic Proteinopathy mechanism in CANVAS. Various biophysical and biomolecular assays characterized the interactions of three aggregation-prone RNA-binding proteins (RBPs): heterogeneous nuclear ribonucleoprotein H1/F (hnRNP H1/F), and DGCR8 with different pathogenic repeats [(AAGGG)9] in vitro, further affirming the hypothesis. The biophysical observations are further supported by molecular dynamics analysis and cell-based studies, putting us a step closer to elucidating the pathological mechanism(s) in CANVAS neuropathy, paving the way for the development of innovative therapeutic interventions.

Predictive Analysis of Yi-Gai-San's Multifaceted Mechanisms for Tremor-dominant Parkinson's Disease via Network Pharmacology and Molecular Docking Validation.

Based on comprehensive network-pharmacology and molecular docking analysis, this study was intended to unveil the multiple mechanisms of Yi- Gai-San (YGS) in treating the tremor-dominant subtype of Parkinson's disease (PD-DT). The compounds of YGS were meticulously analyzed, selected, and standardized with references to their pharmacological attributes. Its components included Gouteng (Uncaria rhynchophylla), Chaihu (Radix Bupleuri), Chuanxiong (Chuanxiong Rhizoma), Danggui (Angelicae sinensis radix), Fuling (Wolfiporia extensa), Baizhu (Atractylodis macrocephalae rhizoma), and Gancao (Licorice, Glycyrrhizae radix). We identified 75 active compounds within YGS. From these, we predicted 110 gene targets, which exhibited a direct association with PD-DT. PPI network results highlighted core target proteins, including TP53, SLC6A3, GAPDH, MAOB, AKT, BAX, IL6, BCL2, PKA, and CASP3. These proteins potentially alleviate PD-DT by targeting inflammation, modulating neuronal cell apoptosis, and regulating the dopamine system. Furthermore, GO and KEGG enrichment analyses emphasized that YGS might influence various mechanisms, such as the apoptotic process, mitochondrial autophagy, Age-Rage signaling, and dopaminergic and serotonergic synapses. The core proteins from the PPI analysis were selected for the docking experiment. The docking results demonstrated that the most stable ligand-receptor conformations were kaempferol with CASP3 (-9.5 kcal/mol), stigmasterol with SLC6A3 (-10.5 kcal/mol), shinpterocarpin with BCL2L1 (-9.6 kcal/mol), hirsutine with MAOB (-9.7 kcal/mol), hederagenin with PRKACA (-9.8 kcal/mol), and yatein with GAPDH (-9.8 kcal/mol). These results provide us with research objectives for future endeavors in extracting single compounds for drug manufacturing or in-depth studies on drug mechanisms. From these computational findings, we suggested that YGS might mitigate PD-DT via "multi-compounds, multi-targets, and multi-pathways."

In silico studies on nicotinamide analogs as competitive inhibitors of nicotinamidase in methicillin-resistant Staphylococcus aureus.

Nicotinamidase/PncA is a member of the hydrolase enzyme family, catalyzing the de-amidation of nicotinamide (NM) to nicotinic acid (NA) via salvage pathway. Products are fed into Preiss-Handler pathway for NAD+ biosynthesis which is an important enzyme cofactor and crucial for redox balance in microorganisms. Pathogens like methicillin-resistant Staphylococcus aureus (MRSA) are NAD+ auxotroph and rely on their host environment for NAD+ precursors to synthesize NAD+. Mutations in nicotinamidase/PncA have been reported to be associated with resistance to pyrazinamide (PZA), a front-line anti-tubercular drug, underlying its importance as an important link in NAD+ biosynthesis network in pathogenic organisms such as MRSA. The conserved features of PncA and essentiality of salvage route in MRSA and the absence of this enzyme in humans and other eukaryotes are attractive options to explore therapeutics against this target. In this work, we have screened novel substrate analogs from the PubChem database using virtual screening approaches employing fingerprint tanimoto-based 2D similarity search against Staphylococcus aureus PncA (SaPncA). Identified compounds were further assessed using molecular dynamics simulations to investigate conformational stability and structural integrity. We propose two analogs, namely L28 and L33 with greater stability, favorable binding and strong binding free energies in MM-PBSA calculations. The strategy could provide an important clue in developing similar compound scaffolds as potent drug-like molecules against MRSA and other pathogenic species harboring this enzyme. Smaller scaffolds of these molecules could be attractive options for fragment-based derivatization for inhibitor discovery.

Unraveling the physiochemical characteristics and molecular insights of Zein protein through structural modeling and conformational dynamics: a synergistic approach between machine learning and molecular dynamics simulations

This research article presents a comprehensive investigation into the three-dimensional structure, physicochemical characteristics and conformational stability of the Zein protein. Machine learning (ML) based homology modeling approach, was employed to predict the 3D structure of Zein protein. Convolutional neural networks (CNNs) were utilized for refining the model, capturing complex spatial features and improving decoy refinement. The predicted 3D structure of Zein protein showed a high-confidence score, i.e. C-score of 0.96. Physiochemical characteristic was also analyzed to investigate its protonation and deprotonation behavior across a range of pH values. A comprehensive analysis of the titration curve and electrostatic charges was performed to uncover valuable molecular insights into the zein protein’s charge distribution, electrostatic interactions and potential conformational changes. Molecular dynamics (MD) simulations were performed to analyze the zein structural behavior under different pH values (2.0, 4.5, 6.8, 10.0 and 12.5), ionic strengths (0 mM, 25 mM, 50 mM, 75 mM, 100 mM) and temperatures (300K, 350K, 375K). Our results demonstrated the influence of these factors on zein protein’s stability and conformational dynamics. At extreme pH values of 2.0 and 12.5, the Zein protein exhibited increased structural deviations and potential unfolding, while intermediate pH values closer to the protein’s isoelectric point (pI) demonstrated more compact and stable conformations. Analysis of root mean square deviation, radius of gyration, solvent accessible surface area and Ramachandran plot provided clear understandings of the protein’s compactness and surface exposure, confirming the impact of pH, ionic strength and temperature on the protein’s conformation.

Transition Path Dynamics of Non-Markovian Systems across a Rough Potential Barrier.

Transition paths refer to rare events in physics, chemistry, and biology where the molecules cross barriers separating stable molecular conformations. The conventional analysis of the transition path times employs a diffusive and memoryless transition over a smooth potential barrier. However, it is widely acknowledged that the free energy profile between two minima in biomolecular processes is inherently not smooth. In this article, we discuss a theoretical model with a parabolic rough potential barrier and obtain analytical results of the transition path distribution and mean transition path times by incorporating absorbing boundary conditions across the boundaries under the driving of Gaussian white noise. Further, the influence of anomalous dynamics in rough potential driven by a power-law memory kernel is analyzed by deriving a time-dependent scaled diffusion coefficient that coarse-grains the effects of roughness, and the system's dynamics is reduced to a scaled diffusion on a smooth potential. Our theoretical results are tested and validated against numerical simulations. The findings of our study show the influence of the boundary conditions, barrier height, barrier roughness, and memory effect on the transition path time distributions in a rough potential, and the validity of the scaling diffusion coefficient has been discussed.

Conformational plasticity links structural instability of NAA10F128I and NAA10F128L mutants to their catalytic deregulation

The acetylation of proteins' N-terminal amino groups by the N-acetyltransferase complexes plays a crucial role in modulating the spatial stability and functional activities of diverse human proteins. Mutations disrupting the stability and function of NAA10 result in X-linked rare genetic disorders. In this study, we conducted a global analysis of the impact of fifteen disease-associated missense mutations in NAA10. The analyses revealed that mutations in specific residues, such as Y43, V107, V111, and F128, predictably disrupted interactions essential for NAA10 stability, while most mutations (except R79C, A111W, Q129P, and N178K) expectedly led to structural destabilization. Mutations in many conserved residues within short linear motifs and post-translational modification sites were predicted to affect NAA10 functionality and regulation. All mutations were classified as pathogenic, with F128I and F128L identified as the most destabilizing mutations. The findings show that the F128L and F128I mutations employ different mechanisms for the loss of catalytic activities of NAA10F128L and NAA10F128I due to their structural instability. These two mutations induce distinct folding energy states that differentially modulate the structures of different regions of NAA10F128L and NAA10F128I. Specifically, the predicted instability caused by the F128I mutation results in decreased flexibility within the substrate-binding region, impairing the substrate peptide binding ability of NAA10F128I. Conversely, F128L is predicted to reduce the flexibility of the region containing the acetyl-CoA binding residues in NAA10F128L. Our study provides insights into the mechanism of catalytic inactivation of mutants of NAA10, particularly elucidating the mechanistic features of the structural and functional pathogenicity of the F128L and F128I mutations.

Assessing the Manufacturability and Critical Quality Attribute Profiles of Anti-IL-8 Immunoglobulin G Mutant Variants.

Early-phase manufacturability assessment of high-concentration therapeutic monoclonal antibodies (mAbs) involves screening of process-related risks impacting their translation into the clinic. Manufacturing a mAb at scale relies on cost-effective and robust approaches to derisk manufacturability parameters, such as viscosity, conformational stability, aggregation, and process-related impurities. Using a panel of model anti-IL-8 IgG1 mutants, we investigate upstream and downstream processability, phase behavior, and process-related impurities. We correlate trends in the biophysical properties of mAbs with their cell growth, expression, filtration flux, solubility, and post-translational modifications. We find significant trends in increased relative free light chain expression with heavy chain mutants and detect a requirement for adjusted operation pH for cation exchange polishing steps with charge-altering variants. Moreover, trends between phase stability and high-concentration viscosity were observed. We also investigated unique correlations between increased glycosylation and biophysical behavior. Further in-depth analysis and modeling are required to elucidate the impact of the mAb sequence on the metabolism of the expression system, solubility limits, and alternative gelation models as future directions.

Conformational Changes and Coordination Stability of Flexible Tripeptides During Ni(II)-mediated Self-assembly.

The rational design of artificial supramolecular structures with specific properties and functions hinges the comprehensive understanding of the coordination and noncovalent interactions driving self-assembly. Herein, the self-assembly of supramolecular systems through octahedral coordination between Ni(II) ions and a flexible tripeptide was theoretically investigated using quantum chemical calculations. These calculations utilized the B3LYP functional with the polarizable continuum model. Our results indicate that tridentate sites have a greater propensity for coordination, and that the presence of chloride anions and conformational shifts enhance bidentate and monodentate coordination. Insights into the effect of counter anions on the stability of octahedral coordination and the prerequisites for self-assembly were gained by determining the stable conformation and potential reaction pathways of the tripeptide before and after adding chloride anions through an efficient automated conformational search. The formation of intramolecular hydrogen bonding interactions during the conformational changes was also studied using model calculations. Possible processes for initial self-assembly of tripeptide were proposed. This study enhances the fundamental understanding of the conformational behavior of building blocks during supramolecular formation and advance the potential for constructing future bioinspired complexes.

Both chebulagic acid and punicalagin inhibit respiratory syncytial virus entry via multi-targeting glycoprotein and fusion protein.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections, with no currently available small-molecule drugs that are both safe and effective. A major obstacle in antiviral drug development is the rapid emergence of drug-resistant viral strains. Targeting multiple viral compounds may help mitigate the development of resistance. Herein, we conducted a drug screening using the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to identify compounds that simultaneously target the RSV fusion (F) protein, glycoprotein (G), and the host heparan sulfate proteoglycans (HSPGs). From this screening, 10 candidate compounds were identified for their ability to interact with all three targets. Among these 10 candidates, chebulagic acid (CHLA) and punicalagin (PUG) demonstrated the most potent inhibition of RSV replication. In vitro dose-response assays confirmed the antiviral efficacy of CHLA (IC50: 0.07864 µM) and PUG (IC50: 0.08065 µM). Further experiments revealed both CHLA and PUG disrupt RSV attachment and membrane fusion by targeting the RSV-F and G proteins, rather than HSPG. Notably, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with docking assays predicting their binding sites at cysteines 176 and 182. Additionally, CHLA enhanced the conformational stability of the RSV-F protein before fusion. In an in vivo study, both CHLA and PUG were shown to alleviate RSV-induced pulmonary pathology by reducing viral titers, mitigating lung injury, and suppressing the inflammatory responses in the lungs. Our findings suggest that CHLA and PUG hold potential as therapeutic agents for RSV infection.IMPORTANCEA significant challenge in developing anti-respiratory syncytial virus (RSV) agents is the rapid emergence of resistant viral strains. Designing drugs that target multiple viral components can effectively reduce the likelihood of developing resistant strains. In this study, we screened compounds from the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to simultaneously targe the RSV fusion (F) protein, glycoprotein (G), and host heparan sulfate proteoglycans (HSPGs). Our findings revealed that chebulagic acid (CHLA) and punicalagin (PUG) significantly inhibited RSV replication both in vitro and in vivo and interacted with all three targets. Both CHLA and PUG were able to disrupt RSV attachment and membrane fusion. Mechanistically, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with CHLA also enhancing the conformational stability of the RSV-F protein before fusion. In conclusion, our study suggests that CHLA and PUG hold promise as therapeutic agents against RSV infection.

Experimental and Computational Evidence of a Stable RNA G‐Triplex Structure at Physiological Temperature in the SARS‐CoV‐2 Genome

AbstractRG1 is a quadruplex‐forming sequence in the SARS‐CoV‐2 genome proposed as possible therapeutic target for COVID‐19. We demonstrate that the dominant conformation of RG1 under physiological conditions differs from the parallel quadruplex previously assumed. Through comprehensive investigations employing CD, UV, NMR, DSC, gel electrophoresis, MD simulations, in silico spectroscopy and the use of truncated RG1 sequences, we have identified this stable conformation as an RNA G‐triplex composed of two G‐triads. We believe this previously unreported RNA structure could serve as a novel therapeutic target. Our findings open new avenues for further studies on the presence and biological role of RNA G‐triplexes in vivo.

Direct activation of HSF1 by macromolecular crowding and misfolded proteins.

Stress responses play a vital role in cellular survival against environmental challenges, often exploited by cancer cells to proliferate, counteract genomic instability, and resist therapeutic stress. Heat shock factor protein 1 (HSF1), a central transcription factor in stress response pathways, exhibits markedly elevated activity in cancer. Despite extensive research into the transcriptional role of HSF1, the mechanisms underlying its activation remain elusive. Upon exposure to conditions that induce protein damage, monomeric HSF1 undergoes rapid conformational changes and assembles into trimers, a key step for DNA binding and transactivation of target genes. This study investigates the role of HSF1 as a sensor of proteotoxic stress conditions. Our findings reveal that purified HSF1 maintains a stable monomeric conformation independent of molecular chaperones in vitro. Moreover, while it is known that heat stress triggers HSF1 trimerization, a notable increase in trimerization and DNA binding was observed in the presence of protein-based crowders. Conditions inducing protein misfolding and increased protein crowding in cells directly trigger HSF1 trimerization. In contrast, proteosynthesis inhibition, by reducing denatured proteins in the cell, prevents HSF1 activation. Surprisingly, HSF1 remains activated under proteotoxic stress conditions even when bound to Hsp70 and Hsp90. This finding suggests that the negative feedback regulation between HSF1 and chaperones is not directly driven by their interaction but is realized indirectly through chaperone-mediated restoration of cytoplasmic proteostasis. In summary, our study suggests that HSF1 serves as a molecular crowding sensor, trimerizing to initiate protective responses that enhance chaperone activities to restore homeostasis.

Unraveling the impact of mutations on the functional dynamics, stability, and energetics of dengue virus non-structural protein 1

ABSTRACT The non-structural protein 1 (NS1), a viral toxin, is linked to serious consequences of dengue. Given its crucial role in the viral life cycle, NS1 has been a primary target for antiviral drug development. This study elucidates the mechanistic impact of specific NS1 mutations, V220D and A248V, identified by Tan and colleagues as potential inhibitors of viral replication. We developed an integrated computational framework to analyze these mutations relative to the native NS1 protein. Using conventional all-atom molecular dynamic simulations followed by site-directed in silico mutagenesis, significant alterations in protein structure were observed. Conformational ensembles over time showed average backbone deviations of 0.44 nm and 0.43 nm for V220D and A248V, respectively, compared to 0.37 nm for the wild type. Residue-wise fluctuations were higher in A248V compared to both wild type and V220D systems. Mutation-induced disruptions in the hydrogen bond network and altered protein structure graphs were also revealed. Principal component analysis and free energy landscape assessments showed the wild-type protein had a more constrained and stable conformation, whereas the mutants displayed scattered energy contours, suggesting reduced structural stability. This comprehensive assessment provides deep insight into the structural impact of NS1 mutations, informing future efforts in antiviral drug development targeting NS1.

Pecan (Carya illinoinensis (Wangenh.) K. Koch) nuts as an emerging source of protein: extraction, physicochemical and functional properties.

The increasing demand for sustainable alternatives to traditional protein sources, driven by population growth, underscores the importance of protein in a healthy diet. Pecan (Carya illinoinensis (Wangenh.) K. Koch) nuts are currently underutilized as plant-based proteins but hold great potential in the food industry. However, there is insufficient information available on pecan protein, particularly its protein fractions. This study aimed to explore the physicochemical and functional properties of protein isolate and the main protein fraction glutelin extracted from pecan nuts. The results revealed that glutelin (820.67 ± 69.42 g kg-1) had a higher crude protein content compared to the protein isolate (618.43 ± 27.35 g kg-1), while both proteins exhibited amino acid profiles sufficient for adult requirements. The isoelectric points of protein isolate and glutelin were determined to be pH 4.0 and pH 5.0, respectively. The denaturation temperature of the protein isolate (90.23 °C) was higher than that of glutelin (87.43 °C), indicating a more organized and stable conformation. This is further supported by the fact that the protein isolate had a more stable main secondary structure than glutelin. Both proteins demonstrated improved solubility, emulsifying, and foaming properties at pH levels deviating from their isoelectric points in U-shaped curves. Compared to the protein isolate, glutelin displayed superior water and oil absorption capacity along with enhanced gelling ability. The protein isolate and glutelin from pecan nuts exhibited improved stability and competitive functional properties, respectively. The appropriate utilization of these two proteins will support their potential as natural ingredients in various food systems. © 2024 Society of Chemical Industry.

β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide. It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can be fit into the cavity of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD. Docking studies suggested that the 1:1 inclusion complex is more favorable than higher order complexes due to the steric hindrance and size considerations. The docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CDand HPβ-CD.

Distinct association of HRAS and KRAS with Mn(II) ion illustrated by paramagnetic NMR

Rat sarcoma virus oncogene (RAS) proteins are among crucial oncogenic proteins and are involved in several essential intracellular processes. The RAS protein has an intrinsic metal binding site for Mg2+, which is important for the conformational stability of the active site. Recently, it was reported that a second metal ion binding site, located further from the active site in HRAS (Harvey RAS homolog), binds Ca2+ with millimolar affinity. As one of the most abundant metal ions in cells, Mn2+ is a potential candidate for the second metal ion binding site in RAS proteins. Here, we examined the interaction of Mn2+ with HRAS and KRAS (Kirsten RAS homolog) using high resolution NMR spectroscopy. The NMR data showed that both the second metal ion binding site and the switch I and II regions bind Mn2+ in the RAS proteins. Furthermore, our paramagnetic NMR results disclosed the conformational differences in helix α3 and the following loop between HRAS and KRAS, accompanied by the association with metal ion binding. These results provide new insights into the interaction of RAS proteins and Mn2+ in the respective biological processes in cells.

Structural, electronic, and magnetic properties of binary zigzag antimonene-phosphorene nanoribbons and their mole fractions with different edge passivation: A DFT investigation

The study focuses on binary antimonene-phosphorene, a two-dimensional semiconductor material known for its high carrier mobility, suitable band gap, and strong environmental stability, making it appealing for electronics and spintronics applications. In this study, using density functional theory, we investigated the structural stability and electronic-magnetic properties of zigzag SbP nanoribbons, as well as single Sb and single P nanoribbons. Various edge passivation (H, F, Cl, O, S) are considered, along with different phosphorus mole fractions. The findings show that SbP structures with 25% phosphorus mole fractions, as well as those passivated with various atoms, demonstrate strong conformational stability. SbP nanoribbons passivated with H, F, and Cl exhibit non-magnetic semiconductor behavior, while those passivated with O and S display magnetic metallic properties. Maximal magnetization is observed in SbP nanoribbons passivated with single S atoms, particularly magnetizing both Sb and P atoms at the edges. Additionally, SbP nanoribbons passivated with dual O atoms show negative differential resistivity and a complete spin filtering effect (100%). The study also investigates the variation in magnetization across structures with different phosphorus mole fractions. Overall, the study demonstrates that adjusting phosphorus mole fractions and edge passivation can significantly modify the electronic and magnetic properties of SbP nanoribbons, making them suitable for spintronic nanodevices.

Corannulene-Based Quintuple [6]/[7]Helicenes: Well-Preserved Bowl Core, Inhibited Bowl Inversion and Supramolecular Assembly with Fullerenes.

Herein, corannulene-based quintuple [6]helicenes (Q[6]H-1 and Q[6]H-2) and [7]helicene (Q[7]H) were synthesized via penta-fold Heck and Mallory reaction. Notably, Q[7]H represents the highest reported helicene based on corannulene. X-ray crystallography reveals that Q[6]H-2 adopts a propeller-shaped conformation with a well-preserved corannulene core, while Q[6]H-1 and Q[7]H exhibit quasi-propeller-shaped conformations. Upon heating, conformer Q[6]H-1 undergoes conversion to the thermodynamically more stable conformer Q[6]H-2, whereas conformer Q[7]H remains unchanged due to larger steric congestion. Racemization of the enantiomer of Q[6]H-1 and conformational conversion were observed simultaneously at elevated temperature, with DFT studies indicating a racemization barrier of 32.06 kcal ⋅ mol-1. In contrast, the racemization barrier for Q[6]H-2 was calculated to be 45.46 kcal ⋅ mol-1, indicating exceptional chiral stability. Surprisingly, the bowl inversions of Q[6]H-1 and Q[6]H-2 conformers are somewhat inhibited by the helical blades, whereas this was not observed for other possible conformers of Q[6]H. These results first demonstrated that subtle conformational variations can lead to significant changes in chiral stability and bowl inversions of multiple helicenes. Due to the well-preserved corannulene core, propeller-shaped conformation and electron complementarity, Q[6]H-2 can recognize fullerenes in both solution and solid state, which is a rare instance of co-crystallization assembly between multiple helicenes and fullerenes.