Conformational Analysis Research Articles

Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings

Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings

New 24-Membered Macrolactines from an Arctic Bacterium Bacillus amyloliquefaciens SCSIO 41392 and Their Anti-Pathogenicity Evaluation

Three new 24-membered macrolactines, amylomacrolactines A–C (1–3), along with two known compounds 4 and 5, were isolated from the Arctic bacteria Bacillus amyloliquefaciens SCSIO 41392. The configurations of 1–3 were assigned by a combination of coupling constants, NOESY, and analysis of MM2-optimized conformation, as well as by comparison with reports in the literature. Compounds 1 and 2 showed quorum sensing (QS) inhibitory activities against the Pseudomonas aeruginosa (P. aeruginosa) PQS system and suppressed PQS-regulated virulence factor pyocyanin synthesis. In addition, compounds 3–5 affected the production of another essential virulence factor, siderophore of pyoverdine (PVD), in P. aeruginosa. More importantly, compound 5 showed an anti-biofilm activity against P. aeruginosa. Altogether, the isolated compounds displayed multiple bacterial virulence inhibition activities, which is worthy of further exploration for novel analogues in antimicrobial drug development.

Molecular Dynamics Simulation Study on the Structural and Thermodynamic Analysis of Oxidized and Unoxidized Forms of Polyaniline.

The conducting polymer polyaniline (PANI) has shown significant interest for the development of electrified membranes (EMs) with superior antifouling characteristics. However, the blending and doping of PANI with other polymers and nanomaterials highly influence the properties of the membrane surface. PANI exists in two forms: oxidized, known as emeraldine salt (ES), and unoxidized, referred to as emeraldine base (EB). Therefore, understanding the different forms of PANI and the variations between the oxidized and unoxidized forms along the length of the polymer chain is intriguing. In this paper, we present the design of a novel copolymer consisting of EB and ES monomers with varying charge densities and different segmental arrangements. We present various intra- and intermolecular structural properties of the PANI chains using all-atom molecular dynamics (MD) simulations. Herein, we present a detailed conformational free energy analysis to understand the conformational transitions of the PANI chains. Our results show increased radius of gyration (Rg) values with increased charge density. Furthermore, we also present the H-bonding, free energy analysis, reduced density gradient (RDG), and solvent-accessible surface area (SASA) values for the observed conformational transitions of PANI. Therefore, these observations are crucial in understanding the complex behavior of chains for designing target-specific polymeric materials.

Short Lysine-Containing Tripeptide as Analgesic Substance: The Possible Mechanism of Ligand–Receptor Binding to the Slow Sodium Channel

A possible molecular mechanism of the ligand–receptor binding of Ac-Lys-Lys-Lys-NH2 (Ac-KKK-NH2) to the NaV1.8 channel that is responsible for nociceptive signal coding in the peripheral nervous system is investigated by a number of experimental and theoretical techniques. Upon Ac-KKK-NH2 application at 100 nM, a significant decrease in the effective charge carried by the NaV1.8 channel activation gating system Zeff is demonstrated in the patch-clamp experiments. A strong Ac-KKK-NH2 analgesic effect at both the spinal and supraspinal levels is detected in vivo in the formalin test. The distances between the positively charged amino groups in the Ac-KKK-NH2 molecule upon binding to the NaV1.8 channel are 11–12 Å, as revealed by the conformational analysis. The blind docking with the NaV1.8 channel has made it possible to locate the Ac-KKK-NH2 binding site on the extracellular side of the voltage-sensing domain VSDI. The Ac-KKK-NH2 amino groups are shown to form ionic bonds with Asp151 and Glu157 and a hydrogen bond with Thr161, which affects the coordinated movement of the voltage sensor up and down, thus modulating the Zeff value. According to the results presented, Ac-KKK-NH2 is a promising candidate for the role of an analgesic medicinal substance that can be applied for pain relief in humans.

Investigate the binding of pesticides with the TLR4 receptor protein found in mammals and zebrafish using molecular docking and molecular dynamics simulations.

The widespread use of pesticides poses significant threats to both environmental and human health, primarily due to their potential toxic effects. The study investigated the cardiovascular toxicity of selected pesticides, focusing on their interactions with Toll-like receptor 4 (TLR4), an important part of the innate immune system. Using computational tools such as molecular docking, molecular dynamics (MD) simulations, principal component analysis (PCA), density functional theory (DFT) calculations, and ADME analysis, this study identified C160 as having the lowest binding affinity (-8.2kcal/mol), followed by C107 and C165 (-8.0kcal/mol). RMSD, RMSF, Rg, and hydrogen bond metrics indicated the formation of stable complexes between specific pesticides and TLR4. PCA revealed significant structural changes upon ligand binding, affecting stability and flexibility, while DFT calculations provided information about the stability, reactivity, and polarity of the compounds. ADME studies highlighted the solubility, permeability, and metabolic stability of C107, C160, and C165, suggesting their potential for bioavailability and impact on cardiovascular toxicity. C107 and C165 exhibit higher bioactivity scores, indicating favourable absorption, metabolism, and distribution properties. C165 also violated rule where molecular weight is greater than 500g/mol. Further, DFT and NCI analysis of post MD conformations confirmed the binding of ligands at the binding pocket. The analysis shed light on the molecular mechanisms of pesticide-induced cardiovascular toxicity, aiding in the development of strategies to mitigate their harmful effects on human health.

Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis.

The structure of iriomoteolide-1a, a marine macrolide with potent cytotoxic activity against human cancer cells, has been under scrutiny for more than a decade since the first total synthesis of the proposed structure was achieved by Horne. Here we disclose the correct structure of iriomoteolide-1a. Given a huge number of possible stereoisomers, we adopted an integrated strategy toward the structure elucidation of iriomoteolide-1a: (1) NMR spectroscopic analysis/molecular mechanics-based conformational analysis for configurational reassignment of the macrolactone domain; (2) model synthesis for validating the reassigned configuration of the macrolactone domain; (3) GIAO NMR calculation/DP4+ analysis of side chain stereoisomers; and (4) total synthesis of the most likely structure. Moreover, the correct structure of iriomoteolide-1b, a natural congener, was also determined by an integration of NMR spectroscopic analysis, GIAO NMR calculation/DP4+ analysis, and total synthesis.

NMR Coupling Constants, Karplus Equations, and Adjusted MD Statistics: Detecting Diagnostic Torsion Angles for the Solution Geometry of 6-[α-d-Mannopyranosyl]-d-Mannopyranose (Mannobiose).

The quantitative solution conformations of 2-(hydroxymethyl)-tetrahydropyran, α-methyl-d-mannopyranoside, and 6-[α-d-mannopyranosyl]-d-mannopyranose (mannobiose) are described. Parametrized Karplus equations for redundant spin pairs across the terminal ω-torsion and the glycosidic ω-torsion for mannobiose are developed, including ω/θ-hypersurfaces for the terminal hydroxymethylene group. Experimental NMR data, algorithmic spectral simulation (clustered Hamiltonian method), molecular dynamics (MD) simulations (GLYCAM06), energy minimizations by DFT, and adjusted torsion angle populations weighted over the Karplus-type equations are used. We demonstrate that spectral simulation is a powerful tool in the refinement of initial J values obtained from static GAIO DFT calculations. We also show that only as few as one of multiple redundant torsions can be diagnostic for conformational analysis of the disaccharide.

Synthesis, C-N/N-N bond conformational analysis and evaluation of naphtho[2,3-d][1,2,3]triazole-4,9-dione tethered N-acyl hydrazones as α-amylase inhibitors: Insights from molecular modeling and ADMET analysis

In an effort to expand the repertoire of potent α-amylase inhibitors, we sought to develop novel inhibitors by combining 1,4-naphthoquinone, 1,2,3-triazole, and N-acyl hydrazone scaffolds in a single matrix. To achieve this, twelve novel naphtho[2,3-d][1,2,3]triazole-4,9‑dione tethered N-acyl hydrazones were synthesized through condensation reaction of 2-(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-1-yl)acetohydrazide with various substituted aryl aldehydes. Structural elucidation for all the compounds was performed using 1D, 2D-NMR, FTIR, and mass spectral analyses. The synthesized molecules were evaluated for their ability to inhibit α-amylase activity using acarbose as the standard drug. All the derivatives exhibited potent inhibition of α-amylase, with IC50 values ranging between 17.26 ± 0.07 to 25.62 ± 0.03 μg/mL. Notably, compound 9c possessing –meta substituted –NO2 group displayed the highest activity (IC50 = 17.26 ± 0.07 μg/mL) among the series. Structure-activity relationship (SAR) revealed the pivotal role of aryl ring substitutions in determining inhibitory efficacy. To validate these findings and to assess the binding stability of 9c within the catalytic site α-amylase dervied for A. oryzae (PDB ID:7TAA), in silico studies were performed. The compound 9c effectively occupies the enzyme's active pocket, with minimal RMSD fluctuations observed over 100 ns simulation, indicating stable protein-ligand complex. ADMET predictions suggested favorable drug-like properties, underscoring the potential of these compounds as novel α-amylase inhibitors for managing type 2 diabetes mellitus

A Simple Analysis of the Second (Extra) Disulfide Bridge of VHHs.

Camelids produce a special type of antibody, known as VHHs, that has lost the VL domain, providing a more optimised VH domain. This particular highly stable antibody domain has interesting properties for biotechnological development. Ordinarily, those molecules possess only one disulphide bridge, but surprisingly, at least a quarter of these VHHs have a second one. Curiously, this does not seem to be essential for the stability and the function of this domain. In an attempt to characterise precisely the role and impact of this disulphide bridge at the molecular level, several in silico mutants of a VHH were created to disrupt this second disulphide bridge and those systems were submitted to molecular dynamics simulation. The loss of the second disulphide bridge leads to an increase in the flexibility of CDR1 and CDR3 and an unexpected rigidification of CDR2. Local conformational analysis shows local differences in the observed protein conformations. However, in fact, there is no exploration of new conformations but a change in the equilibrium between the different observed conformations. This explains why the interaction of VHHs is not really affected by the presence or absence of this second bridge, but their rigidity is slightly reduced. Therefore, the additional disulphide bridge does not seem to be an essential part of VHHs function.

The vibrational circular dichroism exciton coupling in single-bond C–O stretching vibrations of p-menthene derivatives

The exciton coupling (EC) phenomenon becomes a valuable tool for the absolute configuration (AC) determination of organic molecules when an interaction between two strategically located chromophores in a molecule is evidenced by circularly polarized radiation. Besides the widely used exciton chirality method in electronic circular dichroism, the technique has been also developed for vibrational circular dichroism (VCD). Notably, the information provided by CO stretching vibrations (1680−1800 cm−1) in VCD have demonstrated high applicability. However, reported theoretical approaches have warned about the adequate interpretations of the EC phenomenon since analyzed bisignate bands could be associated with other vibrations. The current paper experimentally addresses the problem to expand the criteria for using EC data in AC determinations. Herein, the VCD exciton coupling (VCDEC) methodology is extended to the analysis of C–O stretching vibrations (1100–1300 cm−1) to uncover their possible use in AC determinations, as well as to reveal the specific contribution of the EC related to C–O vibrations when experimental parameters are considered. To this aim, naturally occurring p-menthene alcohols 1–4 isolated from Ageratina glabrata were previously used to prepare acetates 5 and 6, and acetonides 7 and 8, and now, to prepare carbonates 9–11. Density functional theory (DFT) calculations, including the IR and VCD spectra of the seven derivatives (5–11), were carried out to reinforce the conformational and configurational analysis, while the experimental VCD spectra of 5–7, 9, and 11 demonstrated the presence of C–O couplets. A systematic analysis of these bands, including the Δε value at alpha and beta state (Δεα, Δεβ, respectively), the amplitude of EC (A = ∑ǀΔεǀ) value, the couplet period (L =v‾Δεβ − v‾Δεα) value, the specific area of C–O at couplet (S = Σf(x)(u2)), and the percentage of area related to EC from C–O (S%) were considered. These experimental results were directly related to dihedral angles (θ) from simplistic models to establish the AC. The results suggested that A, Cp, S, and S% parameters are deeply related to the nature of the chromophores. Thereby, adequate molecular structural moieties should be chosen for AC determination when using the EC methodology.

Identification of novel brain penetrant GSK-3β inhibitors toward Alzheimer’s disease therapy by virtual screening, molecular docking, dynamic simulation, and MMPBSA analysis

One of the significant therapeutic targets for Alzheimer’s disease (AD) is Glycogen Synthase Kinase-3β (GSK-3β). Inhibition of GSK-3β can prevent hyperphosphorylation of tau, and thus prevent formation and accumulation of neurofibrillary tangles and neuropil threads that block intracellular transport, trigger unfolded protein response, and increase oxidative stress, cumulatively leading to neurodegeneration. In this study, we have performed structure-based virtual screening of two small-molecule libraries from ChemDiv CNS databases using AutoDock Vina to identify hit molecules based on their binding affinities compared to that of an established GSK-3β inhibitor, indirubin-3’-monoxime (IMO). Pharmacoinformatic screening on SwissADME and pkCSM servers enabled identification of lead molecules with favorable pharmacoinformatic properties for drug likeliness, including blood brain barrier (BBB) permeability. Further, molecular dynamic simulations identified six candidate lead molecules that show stable complex formation with GSK-3β in dynamic state under physiological conditions. Principal component analysis of the dynamic state was used to plot Free Energy Landscapes (FELs) of GSK-3β-ligand complexes. STRIDE secondary structure analysis of the lowest energy conformations identified from FEL plots, and binding free energy calculations by Molecular Mechanics Poisson-Boltzmann Surface Area ((ΔGbind )MM-PBSA) of the simulation trajectories led to the identification of two ligands as potential lead molecules having favorable free energy landscape profiles as well as significantly lower (ΔGbind )MM-PBSA in dynamic state compared to that of reference inhibitor IMO. Hence, this study identifies two novel brain penetrant GSK-3β inhibitors that are likely to have therapeutic potential against Alzheimer’s disease.

Temperature-Dependent Rotation of Protonated Methyl Groups in Otherwise Deuterated Proteins Modulates DEER Distance Distributions

AbstractTemperature-dependent DEER effects are observed as a function of methyl rotation by either leucine- or nitroxide-specific protonated methyl groups in an otherwise deuterated background. Both species induce a site-specific enhancement in the apparent Tm relaxation of the paramagnetic nitroxide label. The presence of a single protonated methyl group in close proximity (4–10 Å) to only one of the two nitroxide rotamer ensembles in AviTagged immunoglobulin-binding B domain of protein A results in a selective and substantial decrease in Tm, manifested by differential decay of the peak intensities in the bimodal P(r) distance distribution as a function of the total dipolar evolution time, temperature, or both. The temperature-dependent differential decay of the individual distance components was globally analyzed by fitting the DEER dipolar time traces to a three-site jump model that is defined by the activation energy of leucine- or nitroxide-specific methyl rotation. Temperature-assisted Tm filtering will capture the DEER structural analysis of biomolecular systems heterogenic conformations, including complexes involving multimeric proteins.

Advancing Protein Analysis: A Low-Pressure Drift Tube Orbitrap Mass Spectrometer for Ultraviolet Photodissociation-Based Structural Characterization.

Owing to its ability to generate extensive fragmentation of proteins, ultraviolet photodissociation (UVPD) mass spectrometry (MS) has emerged as a versatile ion activation technique for the structural characterization of native proteins and protein complexes. Interpreting these fragmentation patterns provides insight into the secondary and tertiary structures of protein ions. However, the inherent complexity and diversity of proteins often pose challenges in resolving their numerous conformations. To address this limitation, we combined UVPD-MS with drift tube ion mobility, offering potential to acquire conformationally selective MS/MS information. A low-pressure drift tube (LPDT) Orbitrap mass spectrometer equipped with 193 nm UVPD capabilities enables the analysis of protein conformers through the analysis of arrival time distributions (ATDs) of individual fragment ions. ATDs of fragment ions are compared for different backbone cleavage sites of the protein or different precursor charge states to give information about regions of potential folding or elongation. This integrated platform offers promise for advancing our understanding of protein structures in the gas phase.

Using reverse vaccinology techniques combined with B-cell epitope prediction to screen potential antigenic proteins of the bovine pathogen Clostridium perfringens type A

Clostridium perfringens type A frequently causes necrohaemorrhagic enteritis in cattle, a rapidly progressing disease with a high mortality rate, thus inflicting substantial economic losses in the cattle industry. Effective prevention and control of this disease rely on rapid detection and vaccination strategies, making the screening of antigenic proteins with diagnostic and vaccine potential particularly crucial. In this study, we conducted a pangenomic analysis of 15 bacterial strains, grounded in traditional reverse vaccinology and supplemented with B-cell linear and conformational epitope analysis tools. This approach led to the identification of 2304 core genes and 3606 accessory genes, among which 58 surface-exposed proteins, encoded by core genes, were identified Proteins lacking tertiary structure information were predicted via AlphaFold2, ultimately identifying four target proteins and 14 candidate proteins enriched with linear and conformational epitopes, including virulence proteins such as alpha-toxin, theta-toxin, and alpha-clostripain, and extracellular solute-binding proteins, rhodanese-like proteins, and the accessory gene-encoded lysozyme inhibitor LprI family protein. Our findings demonstrate that the combined use of multiple B-cell epitope analysis tools can help overcome the limitations of any single tool. The proteins selected in this study offer valuable references for rapid diagnostics and the development of genetically engineered vaccines.

Effect of conformational landscape on the polymorphism and monomorphism of tizanidine cocrystallization outcomes

Molecular conformational diversity plays a crucial role in both polymorphic nucleation and cocrystal formation during the cocrystallization process. However, the relationship between molecular conformation and cocrystallization polymorphism is not well-explored. Herein, the impact of molecular conformational landscapes on cocrystallization outcomes was investigated using tizanidine (TZND) as model compound. Four coformers, namely maleic acid (MA), salicylic acid (SA), p-hydroxybenzoic acid (pHBA), and heptanedioic acid (HDA), were employed and five salt forms were developed for the first time. Compared with TZND, all five salts showed significantly improved water solubility and dissolution rate. The cocrystallization behavior of TZND varied with each coformer: MA exhibited solvent-dependent polymorphism, while SA, pHBA, and HDA showed solvent-independent monomorphism. Crystal structure and conformational analyses revealed the conformational variation of TZND across different cocrystallization outcomes. Molecular dynamics simulations and quantum chemical calculations demonstrated that the interplay between solvent effects and coformer interactions determines the dominant conformations of TZND. The cocrystallization nucleation process was also examined, and the molecular mechanism that explains both polymorphism and monomorphism in the cocrystallization of TZND was proposed.

Lanthanum doped hafnium oxide thin films deposited on a lateral high aspect ratio structure using atomic layer deposition: A comparative study of surface composition and uniformity using x-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry

Hafnium oxide (HfO2) thin films doped with lanthanum (La) can achieve ferroelectricity, making the material applicable in transistor and memory technologies. To downscale future devices in the semiconductor industry, the application of the doped HfO2 material requires deposition on complex microscopic three-dimensional (3D) structures. A widely used process for the preparation of doped HfO2 thin films is atomic layer deposition (ALD). With 3D geometries, it is challenging to deposit materials homogeneously and to effectively characterize them. To forego the difficulties in film characterization, two-dimensional (2D) PillarHall lateral high aspect ratio (LHAR) test structures are used. These structures expose a lateral surface to facilitate the conformality analysis of thin films deposited using two different ALD processes. In this work, we aim to further advance the arsenal of analysis techniques used to characterize La doped HfO2 thin films by using x-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to analyze uniformity and composition. The XPS technique can be applied and established as a method for the optimal analysis of thin films deposited on LHAR structures. Both techniques provide a complementary analysis of material formation, elemental distribution, measurement along the LHAR depth range, and can probe differences between deposition processes.

Molecular nano-I-beam class of materials: options based on configuration, first principles-based optimization and properties

Nanotubes showed merits including high structural strength-to-weight ratio. However, tubes are less favored regarding stiffness and strength. Nano-I-beams are proposed for improved nano-mechanics. Computationally, the study proposes novel molecular designs of I-beam-like shaped structures. A conformation analysis, molecular dynamics and first principles-based optimization are presented. The study proposes options based on the configuration of the molecular nano-I-beam structure providing less number of planes of symmetry and hence more stability than nanotube-like structures. These designs feature a unique geometrical differentiator of having the walls of the out-of-plane hexagonal motif-based molecular nano-I-beam (C60H46) inclined with different inclination angles enabling promising properties. The stability of the proposed nano-I-beam is proved on par with the corresponding nanotube-like structure. First principles-based evidence is provided on the comparable polarizability and the comparable ability to store energy of the supercell of the crystalline slab nano-I-beam in comparison with the corresponding nanotube. A proposed hybrid octa-hexagonal-cubic molecular nano-I-beam (C24H12) remedies the nano-buckling observed in the alike square-octagonal nanostructure. The molecular nano-I-beam exhibits intrinsic switchability that enables the nano-I-beam to be a topological semiconductor/insulator. The results show promising electronic and elastic properties of the proposed nano-I-beams that suit several applications such as their use in capacitors, transistors, insulators, batteries, quantization-based nano-devices, solid lubricant additive to grease, toughening fibers of nanocomposites, hydrophobic films, emissions adsorbents, catalytic sensors, PAH materials for space, and sustainable energy. The molecular nano-I-beam provides the base of the corresponding 2-D crystalline slab nano-I-beams.

Evaluating the accuracy and reliability of AI chatbots in disseminating the content of current resuscitation guidelines: a comparative analysis between the ERC 2021 guidelines and both ChatGPTs 3.5 and 4

Aim of the studyArtificial intelligence (AI) chatbots are established as tools for answering medical questions worldwide. Healthcare trainees are increasingly using this cutting-edge technology, although its reliability and accuracy in the context of healthcare remain uncertain. This study evaluated the suitability of Chat-GPT versions 3.5 and 4 for healthcare professionals seeking up-to-date evidence and recommendations for resuscitation by comparing the key messages of the resuscitation guidelines, which methodically set the gold standard of current evidence and recommendations, with the statements of the AI chatbots on this topic.Methods This prospective comparative content analysis was conducted between the 2021 European Resuscitation Council (ERC) guidelines and the responses of two freely available ChatGPT versions (ChatGPT-3.5 and the Bing version of the ChatGPT-4) to questions about the key messages of clinically relevant ERC guideline chapters for adults. (1) The content analysis was performed bidirectionally by independent raters. The completeness and actuality of the AI output were assessed by comparing the key message with the AI-generated statements. (2) The conformity of the AI output was evaluated by comparing the statements of the two ChatGPT versions with the content of the ERC guidelines.ResultsIn response to inquiries about the five chapters, ChatGPT-3.5 generated a total of 60 statements, whereas ChatGPT-4 produced 32 statements. ChatGPT-3.5 did not address 123 key messages, and ChatGPT-4 did not address 132 of the 172 key messages of the ERC guideline chapters. A total of 77% of the ChatGPT-3.5 statements and 84% of the ChatGPT-4 statements were fully in line with the ERC guidelines. The main reason for nonconformity was superficial and incorrect AI statements. The interrater reliability between the two raters, measured by Cohen’s kappa, was greater for ChatGPT-4 (0.56 for completeness and 0.76 for conformity analysis) than for ChatGPT-3.5 (0.48 for completeness and 0.36 for conformity).ConclusionWe advise healthcare professionals not to rely solely on the tested AI-based chatbots to keep up to date with the latest evidence, as the relevant texts for the task were not part of the training texts of the underlying LLMs, and the lack of conceptual understanding of AI carries a high risk of spreading misconceptions. Original publications should always be considered for comprehensive understanding.

Phosphorus-Nitrogen Compounds: Part 76. Design and Syntheses of Dispiro- and Trispiro(N/N)cyclotriphosphazenes: Conformational and Structural Analyses, Chirality, Electrochemical, Dye-Sensitized Solar Cells, and Bioactivity Studies.

The reactions of monospirocyclotriphosphazenes (1 and 2) with N-methyl-1,3-diaminopropane gave unsymmetrical cis-(3 and 5) and trans-(4 and 6) dispirocyclotriphosphazenes. Trans-cis-trans (tct) (7 and 11), cis-cis-cis (ccc) (8 and 12), trans-trans-cis (ttc) (9 and 13), and cis-trans-trans (ctt) (14) trispirocyclotriphosphazenes were obtained from the reactions of 3 and 5 and 4 and 6 with N-methyl-1,3-diaminopropane. cis-Dispirocyclotriphosphazenes (3 and 5) exist as "pseudomesoracemates", while trans-dispirocyclotriphosphazenes (4 and 6) are in "racemates". The existences of cis-3 and trans-4 as "pseudomesoracemate" and "racemate" were confirmed by 31P NMR spectra recorded by the addition of "chiral solvating agent (CSA)". X-ray crystallography proved that the absolute configurations of each enantiomer of cis-5 and trans-6 are SS' and RS'. Trispirocyclotriphosphazenes tct, ttc, ccc, and ctt exist as racemates, pseudomesoracemate, and meso forms. Furthermore, Hirshfeld surface analysis of the crystal structures of cis-5 and trans-6 revealed that the most significant contribution to crystal packing comes from H···H (58.2 and 57.6%, respectively). An oxidation-reduction wave was detected in the reversible cyclic voltammograms of the phosphazenes. The highest power conversion efficiency in dye-sensitized solar cell studies was obtained with cis-5. Additionally, trans-6 exhibited the lowest minimal inhibitory concentration value (78.1 μM) against Candida tropicalis, and it was observed to cleave pBR322 plasmid DNA.

Targeting Polyprotein to Design Potential Multiepitope Vaccine against Omsk Hemorrhagic Fever Virus (OHFV) by Evaluating Allergenicity, Antigenicity, and Toxicity Using Immunoinformatic Approaches.

Omsk Hemorrhagic Fever Virus (OHFV) is an RNA virus with a single-stranded, positive-sense genome. It is classified under the Flaviviridae family. The genome of this virus is 98% similar to the Alkhurma hemorrhagic fever virus (AHFV), which belongs to the same family. Cases of the virus have been reported in various regions of Saudi Arabia. Both OHFV and AHFV have similarities in pathogenic polyprotein targets. No effective and licensed vaccines are available to manage OHFV infections. Therefore, an effective and safe vaccine is required that can activate protective immunity against OHFV. The current study aimed to design a multiepitope subunit vaccine against the OHFV utilizing several immunoinformatic tools. The polyprotein of OHFV was selected and potent antigenic, non-allergenic, and nontoxic cytotoxic T-lymphocyte (CTL), helper T-lymphocyte (HTL), and linear B-lymphocyte (LBL) epitopes were chosen. After screening, eight (8) CTL, five (5) HTL, and six (6) B cell epitopes were joined with each other using different linkers. Adjuvant human beta defensin-2 was also linked to the epitopes to increase vaccine antigenic and immunogenic efficiency. The designed vaccine was docked with Toll-like receptor 4 (TLR4) as it activates and induces primary and secondary immune responses against OHFV. Codon optimization was carried out, which resulted in a CAI value of 0.99 and 53.4% GC contents. In addition, the construct was blindly docked to the TLR4 immune receptor and subjected to conformational dynamics simulation analysis to interpret the intricate affinity and comprehend the time-dependent behavior. Moreover, it was predicted that immune responses to the developed vaccine construct reported formation of strong humoral and cellular immune cells. Therefore, the proposed vaccine may be considered in experimental assays to combat OHFV infections. Laboratory experiments for the above predictions are essential in order to evaluate the effectiveness, safety, and protective properties of the subject in question.