Conformational Studies Research Articles

Characterisation of a catalytic triad and reaction selectivity in the dual mechanism of the catalyse hydride transfer in xylitol phosphate dehydrogenase

Xylitol is a high-value low-calorie sweetener used as sugar substitute in food and pharmaceutical industry. Xylitol phosphate dehydrogenase (XPDH) catalyses the conversion of d-xylulose 5-phosphate (XU5P) and d-ribulose 5-phosphate (RU5P) to xylitol and ribitol respectively in the presence of nicotinamide adenine dinucleotide hydride (NADH). Although these enzymes have been shown to produce xylitol and ribitol, there is an incomplete understanding of the mechanism of the catalytic events of these reactions and the detailed mechanism has yet to be elucidated. The main goal of this work is to analyse the conformational changes of XPDH-bound ligands such as zinc, NADH, XU5P, and RU5P to elucidate the key amino acids involved in the substrate binding. In silico modelling, comparative molecular dynamics simulations, interaction analysis and conformational study were carried out on three XPDH enzymes of the Medium-chain dehydrogenase (MDR) family in order to elucidate the atomistic details of conformational transition, especially on the open and closed state of XPDH. The analysis also revealed the possible mechanism of substrate specificity that are responsible in the catalyse hydride transfer are the residues His58 and Ser39 which would act as the proton donor for reduction of XU5P and RU5P respectively. The structural comparison and MD simulations displayed a significant difference in the conformational dynamics of the catalytic and coenzyme loops between Apo and XPDH-complexes and highlight the contribution of newly found triad residues. This study would assist future mutagenesis study and enzyme modification work to increase the catalysis efficiency of xylitol production in the industry.

Characterization of conformational transition of polymers with low molecular weights in solutions by fluorescence resonance energy transfer

The conformations of polymers in solutions are of great importance, and scattering techniques prevail in detecting these conformations. However, most studies only focus on polymer species with high molecular weights or those well above their entanglement molecular weights, and studies on polymer solutions with low molecular weights, e.g., lower than 10,000 Da, are lacking. Here, the conformation of low molecular weight polymers in solutions with different concentrations was investigated via fluorescence resonance energy transfer (FRET). Based on a site-specific chromophore-labeling protocol, the conformational information of the polymer was inferred from the end-to-end FRET response. In principle, the FRET efficiency increases with increasing polymer concentration since the size of the polymer coil decreases. For low molecular weight polymers, the trend of the FRET efficiency shows the opposite effect as the polymer concentration increases, which is rationalized by the counterbalance of the intrinsic size contraction (static item) of and terminal diffusion (dynamic item) from the polymer coil. The universality of this law is verified by similar results from the polymethyl methacrylate (PMMA) system. This work provides new efforts for the conformational study of polymer solutions and demonstrates that the diffusion effect should be taken into account for low molecular weight polymers but is negligible for polymers with high molecular weights.

Tiara[5]arenes: Synthesis, Solid-State Conformational Studies, Host-Guest Properties, and Application as Nonporous Adaptive Crystals.

Tiara[5]arenes (T[5]s), a new class of five‐fold symmetric oligophenolic macrocycles that are not accessible from the addition of formaldehyde to phenol, were synthesized for the first time. These pillar[5]arene‐derived structures display both unique conformational freedom, differing from that of pillararenes, with a rich blend of solid‐state conformations and excellent host–guest interactions in solution. Finally we show how this novel macrocyclic scaffold can be functionalized in a variety of ways and used as functional crystalline materials to distinguish uniquely between benzene and cyclohexane.

Tiara[5]arenes: Synthesis, Solid‐State Conformational Studies, Host–Guest Properties, and Application as Nonporous Adaptive Crystals

AbstractTiara[5]arenes (T[5]s), a new class of five‐fold symmetric oligophenolic macrocycles that are not accessible from the addition of formaldehyde to phenol, were synthesized for the first time. These pillar[5]arene‐derived structures display both unique conformational freedom, differing from that of pillararenes, with a rich blend of solid‐state conformations and excellent host–guest interactions in solution. Finally we show how this novel macrocyclic scaffold can be functionalized in a variety of ways and used as functional crystalline materials to distinguish uniquely between benzene and cyclohexane.

Impact of conformational and solubility properties on psycho-activity of cannabidiol (CBD) and tetrahydrocannabinol (THC)

Cannabidiol (CBD) is one among many others identified bioactive cannabinoid derivatives. It is the main component in Cannabis sativum oil and can be applied as potential therapeutic agent. It has not any psychoactive effects such as those caused by tetrahydrocannabinol (THC). The basic difference between CBD and THC is an opened or closed heterocycle ring. A conformational study using quantum chemical calculations was performed to the DFT/B3LYP/6-31G(d,p) level. The high energy barrier values, superior to 20 kcal/ mol, may explain the small ability of the CBD to exhibit psychostimulant effect. This property is controlled by steric hindrance between polar groups and nonpolar moieties. n-Pentyl chain has little influence on conformation of CBD. The conformational search by using a simplified cannabidiol derivative showed that stereo-electronic repulsions are responsible for the limitation on CBD conformations. CBD and THC have the highest lipophilicity values when compared to other agents on central nervous system.

Linking chromatin conformation to gene function.

DNA is highly compressed and packaged as chromatin within the nucleus in eukaryotes. DNA replication, DNA repair and transcription, and other biological processes are precisely regulated or determined by chromatin conformation. Activation or repression of different genes/transcription factors are tightly correlated to their chromatin conformation which contributes to cell self-maintenance, differentiation, specificity and identity. Therefore, the study of bridging chromatin conformation to gene function has became crucial for decoding genetic information and precision biology which is also a great challenge for current genomics research. Here, we review the multiple aspects of chromatin conformation, including its history, characteristics, dynamics and the impact on different dimension-chromatin architecture to gene function. Additionally, we discuss the limitation and challenges of current status of linking chromatin conformation to gene function study. We believe this is informative and foundational in combing the context between chromatin conformation and gene function as reference.

Synthesis, analytical and spectral characterization for new VO (II)‐triazole complexes; conformational study beside MOE docking simulation features

New triazole‐derivatives were synthesized and characterized (spectral, analytical and conformational). After that, the new derivatives were coordinated with VO (II) atom to prepare new series of complexes. Distorted octahedral and square‐pyramidal geometries, were the geometries suggested based on UV‐ Vis and ESR spectra. A neutral poly‐dentate mode of bonding was proposed by 1:1 (M:L), for all complexes. TGA study supports the molecular formula of VO (II) complexes as well as, mass spectral‐analysis that executed for examples. The isotropic, anisotropic, molecular orbital and Hamiltonian parameters were estimated upon ESR spectra, for selected complexes. XRD patterns were executed for three complexes, two among appeared with particulate‐sizes in nanometer‐range. Conformational study was executed for all synthesizes applying RTD‐B3LYP‐FC method. Essential physical parameters were estimated and discussed. MOE‐docking that considered a bright part, was performed over all compounds towards 3s7s and 5jm5, as functional tumor proteins. The docking interaction parameters, introduced strongly some synthesizes to be anti‐tumor agents.

CHROMATIX: computing the functional landscape of many-body chromatin interactions in transcriptionally active loci from deconvolved single cells

Chromatin interactions are important for gene regulation and cellular specialization. Emerging evidence suggests many-body spatial interactions play important roles in condensing super-enhancer regions into a cohesive transcriptional apparatus. Chromosome conformation studies using Hi-C are limited to pairwise, population-averaged interactions; therefore unsuitable for direct assessment of many-body interactions. We describe a computational model, CHROMATIX, which reconstructs ensembles of single-cell chromatin structures by deconvolving Hi-C data and identifies significant many-body interactions. For a diverse set of highly active transcriptional loci with at least 2 super-enhancers, we detail the many-body functional landscape and show DNase accessibility, POLR2A binding, and decreased H3K27me3 are predictive of interaction-enriched regions.

Aqueous-Phase Conformations of Lactose, Maltose, and Sucrose and the Assessment of Low-Cost DFT Methods with the DSCONF Set of Conformers for the Three Disaccharides.

In the present study, we have examined a range of quantum chemistry methods for the calculation of conformers for lactose, maltose, and sucrose. We find that the DSD-PBE-P86/aug'-cc-pVTZ//B3-LYP-D3BJ/6-311+G(2d,p) protocol yields good relative energies in comparison with reference CCSD(T)/CBS//B3-LYP-D3BJ/maug-cc-pVTZ values. We have surveyed a total of ∼550 conformers for the three disaccharides with the chosen DSD-PBE-P86 method in conjunction with continuum aqueous solvation. In each case, the lowest free energy conformer is characterized by hydrogen bond(s) between the two rings. Another finding is that the major contributors to the overall variations in aqueous free energies are the electronic energies and the solvation energies. To facilitate investigations of larger systems, we have compiled the DSCONF set of conformers for the three disaccharides, and we have assessed lower cost methods with this set. We find MS1-D3/6-31+G(2d,p) to be cost-effective and accurate for both geometry optimization and the calculation of relative energies for disaccharides. In addition, we note that MS1-D3 has previously been found to yield good relative energies for the WATER27 set of water clusters. We thus deem this method to be appropriate for the study of saccharide conformations in both gas phase and aqueous solution.

Organocatalysed conjugate addition reactions of aldehydes to nitroolefins with anti selectivity

Catalytic reactions that enable access to different diastereoisomers are important but often difficult to achieve. One long-standing unsolved challenge is the anti-selective conjugate addition reaction between aldehydes and nitroolefins. This organocatalytic transformation is a versatile method for the synthesis of γ-nitroaldehydes and downstream compounds such as pyrrolidines and γ-butyrolactams, which are key moieties in bioactive molecules. Numerous amine catalysts have been developed for this transformation, but all provide syn-configured products. Here, we present a tripeptide as a general catalyst for the synthesis of anti-configured γ-nitroaldehydes. Key to the anti selectivity is the installation of substituents at Cδ of the reactive pyrrolidine of proline to enable the formation of s-cis enamine intermediates. The peptidic catalyst converts different aldehyde and nitroolefin combinations into the products in high yields and stereoselectivities. Conformational and mechanistic studies revealed a Curtin–Hammett scenario for the catalytic system. The strategy provides long-sought-after access to anti-configured γ-nitroaldehydes and a guide for reversing the diastereoselectivity of amine-based organocatalysts. The organocatalysed addition of aldehydes to nitroolefins is an extremely well-studied reaction that almost exclusively provides the syn-configured products. Here a general method to reverse the diastereoselectivity is reported, whereby a tripeptide catalyst consistently provides the anti product with high selectivity.

Diastereoselective Synthesis of Steroid-[60]Fullerene Hybrids and Theoretical Underpinning.

The reaction of C60 with pregnen-20-carboxaldehyde, a biologically active synthetic steroid, by using a 1,3-dipolar cycloaddition reaction (Prato's protocol) results in the formation of pyrrolidine rings bearing a new stereogenic center on the C2 of the five-membered ring. The formation of the fullerene-steroid hybrids proceeds with preference for the Re face of the 1,3-dipole, with formation of a diastereomeric mixture in 73:15 ratio. The investigation of the chiroptical properties of these conjugates allowed determining the absolute configuration of the new fulleropyrrolidines. In addition, a thorough spectroscopical study permitted to determine the structure of the two mono-cycloadducts. The electrochemical properties of the new hybrids were also evaluated by cyclic voltammetry, both systems exhibit three quasi-reversible reduction waves which are cathodically shifted in regard to the parent C60. Theoretical calculations help supporting the experimental data. A conformational study combining semiempirical methods and density functional theory has predicted the most stable diastereomer. On the basis of this agreement, a possible reaction mechanism is presented. Additionally, a molecular docking simulation has been carried out using the HIV-1 protease as receptor, thus paving the way to study the possible application of these stereoisomers in biomedicine.

Electrochemiluminescence Self-Interference Spectroscopy with Vertical Nanoscale Resolution.

Here we report an electrochemiluminescence (ECL) self-interference spectroscopy technique (designated as ECLIS) with spatial resolution in the normal direction of the electrode surface. Self-interference principally originates from the superposition of ECL emitted directly by luminophores and that reflected from electrode surfaces, resulting in a spectrum consisting of orderly distributed peaks. On the basis of this spectrum and theoretical analysis by the matrix propagation model, the distance between luminophores and the electrode surface can be probed with a vertical resolution on the nanometer scale. We demonstrated first in this work that the height of ECL luminophores assembled on the electrode surface using different molecular linkers, such as double-stranded DNA, could be determined, as well as the possible conformation of linker molecules at the surface. Moreover, the thickness of the ECL emitting layer adjacent to the electrode surface was estimated for the classical coreactant ECL systems involving freely diffusing Ru(bpy)32+ and tri-n-propylamine in solutions. The thickness was found to vary from ∼350 nm to nearly 1 μm depending on the concentration of Ru(bpy)32+. We believe that ECLIS with a high vertical resolution will provide an easy way to collect molecular conformation information and study ECL reaction mechanisms at electrode interfaces.

Conformational Mobility Study in Mono Quinone Derivative of Calix[4]arene by Low Temperature NMR Spectroscopy

: Calix[4]monoquinone (3) has been synthesized by oxidation of rigid cone conformation of tripropoxy calix[4]arene (2), and conformational characteristics of this molecule have been studied by means of dynamic nuclear magnetic resonance (DNMR) and HH- correlated nuclear magnetic resonance spectroscopy (HH-COSY NMR). On the basis of the data that have been obtained, free Gibbs energy of activation (ΔG#) for quinone ring interconversion process of 3 was determined 12.3±0.05 Kcal/mol by coalescence approximation method.

Cell-penetrating peptides containing 2,5-diketopiperazine (DKP) scaffolds as shuttles for anti-cancer drugs: conformational studies and biological activity.

A series of linear and cyclic peptidomimetics composed of a cell-penetrating peptide and a non-natural, bifunctional 2,5-diketopiperazine scaffold is reported. Conformational studies revealed well-defined helical structures in micellar medium for linear structures, while cyclic peptidomimetics were more flexible. Biological investigations showed higher membrane-activity of cyclic derivatives allowing their use as shuttles for anti-cancer drugs.

Use of isothermal titration calorimetry to study various systems

Isothermal titration calorimetry (ITC) is a technique that allows precise measurements and a complete thermodynamic description of association, interaction or binding processes. This review will address uses of ITC in studies of self-assemble of monocomponent systems and interacting systems in broad spectrum. It also focuses on use of ITC on conformational study, thermodynamic study, reaction kinetics, adsorption phenomena, etc. ITC studies on the association of different monocomponents such as surfactants and polymers to provide quantitative information on different thermodynamic functions associated with micellization / association (Gibbs energy, enthalpy and entropy). Studies on binding isotherm by ITC provide a comprehensive description of the interaction process. Emphasis will be given to analyze the rapid reaction kinetics with new models. This review stresses the importance of using direct calorimetric measurements to obtain and report accurate thermodynamic data, even in complex systems. These data, whenever possible, should be confirmed and verified with other techniques

JAL-TA9 Inhibits Aggregation of Hprp180-192 through the Cleavage Reaction

We identified that JAL-TA9, a 9-mer synthetic peptide derived from Tob1 protein, possesses catalytic activity and cleaves Aβ42. We also determined that the C-terminal end of Prion protein (PrP) is an essential region for aggregation of PrP using PrP fragment peptides. We investigated the effect of JAL-TA9 on hPrP180-192, which is a fragment peptide derived from human prion protein. Conformational studies were performed using CD analysis. The cleavage reaction was identified using HPLC and MS analyses. JAL TA9 inhibited the formation of aggregated hPrP180-192 and decreased the aggregated hPrP180-192 level through the cleavage reaction. These results indicate that JAL-TA9 could be a promising candidate for developing novel drugs against prion diseases and Alzheimer’s disease.

Escherichia coli O176 LPS structure and dynamics: A NMR spectroscopy and MD simulation study.

A lipopolysaccharide (LPS) molecule is a key component of the bacterial outer membrane used to protect the bacterium and to interact with the environment. To gain insight into its function, the study of the LPS conformation and dynamics at the molecular and cellular levels is necessary, but these highly diverse and dynamic membrane-LPS systems are difficult to study. In this work, by using NMR spectroscopy and molecular dynamics (MD) simulations, we determined the conformational preferences of an E. coli O176 O-antigen polysaccharide at the atomic level. Moreover, we analyzed the use of non-uniform sampling (NUS) for the acquisition of high dynamic range spectra, like 1H,1H-NOESY NMR experiments. A comparison of the effective transglycosidic distances derived from conventional uniformly sampled and NUS 1H,1H-NOESY data showed high similarity under equal measuring time conditions. Furthermore, the experimentally derived internuclear distances of the O-antigen polysaccharide with ten repeating units (RUs) showed very good agreement to those calculated from the MD simulations of the same O-antigen polysaccharide in solution. Analysis of the LPS bilayer simulations with five and with ten RUs revealed that, although similar with respect to populated states in solution, the O-antigen in LPS bilayers had more extended chains as a result of spatial limitations due to close packing. Additional MD simulations of O-antigen polysaccharides from E. coli O6 (branched repeating unit) and O91 (negatively charged linear repeating unit) in solution and LPS bilayers were performed and compared to those of O176 (linear polymer). For all three O-antigens, the ensemble of structures present for the polysaccharides in solution were consistent with the results from their 1H,1H-NOESY experiments. In addition, the similarities between the O-antigen on its own and as a constituent of the full LPS in bilayer environment makes it possible to realistically describe the LPS conformation and dynamics from the MD simulations.

Thermal CFTs in momentum space

We study some aspects of conformal field theories at finite temperature in momentum space. We provide a formula for the Fourier transform of a thermal conformal block and study its analytic properties. In particular we show that the Fourier transform vanishes when the conformal dimension and spin are those of a “double twist” operator ∆ = 2∆ϕ + ℓ + 2n. By analytically continuing to Lorentzian signature we show that the spectral density at high spatial momenta has support on the spectrum condition |ω| > |k|. This leads to a series of sum rules. Finally, we explicitly match the thermal block expansion with the momentum space Green’s function at finite temperature in several examples.

Crystal Structure and 1H NMR Experimental and Theoretical Study of Conformers of 5-Methyl-1-(4’-methylphenylsulfonylamino)-1H-[1,2,3]-triazole-4-carboxylic Acid Ethyl Ester and 5-Methyl-1-(phenylsulfonylamino)-1H-[1,2,3]-triazole-4-carboxylic Acid Ethyl Ester

We reported experimental and theoretical investigation of conformers of 1,2,3-triazole derivatives, substances of exclusively synthetic origin, subject of extensive studies, because of several biological properties, such as antiviral, antimicrobial and antileishmaniasis. We reported molecular/supramolecular X-ray structures of antiophidian compounds I and II. For I and II there are two crystallographic different molecules in the unit cell (A and B). To explore the causes of the similarities in the compound’s crystal structures, intermolecular interactions were explored using the Hirshfeld surface as the fingerprint plots. In addition, density functional theory (DFT) calculations were carried out at the ωB97x-D/6-31G(d,p)-PCM-CHCl3 level aiming to contribute to the interpretation of the experimental data and complement the experimental findings. Two structures named 2A and 5B were found in good agreement with the respective X-ray solid state ones (A and B). Theoretical 1H nuclear magnetic resonance (NMR) spectra calculated for 5B rotated structure (torsion angles deviation around 40° to 90°) was in fine agreement with experimental results (in CDCl3) indicating that the solution molecular structure is considerably different from optimized equilibrium geometries and solid-state structure. Therefore, care is needed when using X-ray structures or DFT geometries to model interaction of drugs with biological targets since significant conformational changes may take place in solution.

Introducing sequential aza-amino acids units induces repeated β-turns and helical conformations in peptides.

A major current issue in medicinal chemistry is the design of small peptide analogues resistant to proteolysis and able to adopt preferential conformations, while preserving the selectivity and efficiency of natural peptides. Whereas the introduction of one aza-Gly in peptides has proven numerous biological and structural interest, the conformational effect of sequential aza-Gly or aza-amino acids bearing side chains has not been investigated. In this work, experimental NMR and X-ray data together with in silico conformational studies reveal that the introduction of two consecutive aza-amino acids in pseudotripeptides induces the formation of stable hydrogen-bonded β-turn structures. Notably, this stabilization effect relies on the presence of side chains on aza-amino acids, as more flexible conformations are observed with aza-Gly residues. Remarkably, a longer aza/aza/α/aza/aza/α pseudohexapeptide containing substituted aza-amino acids adopts repeated β-turns conformations which interconvert with a fully helical structure mimicking a 310 helix.