Search

Finding low-energy structures of ligand-protected clusters is challenging due to the enormous conformational space and the high computational cost of accurate quantum chemical methods for determining the structures and energies of conformers. Here, we adopted and utilized a kernel rigid regression based machine learning method to accelerate the search for low-energy structures of ligand-protected clusters. We chose the Au25(Cys)18 (Cys: cysteine) cluster as a model system to test and demonstrate our method. We found that the low-energy structures of the cluster are characterized by a specific hydrogen bond type in the cysteine. The different configurations of the ligand layer influence the structural and electronic properties of clusters. [ABSTRACT FROM AUTHOR]

An impact of an electronic structure or force field method, gas‐phase thermodynamic correction, and continuum solvation model on organic carbonate clusters (S)n conformational and binding energies is explored. None of the tested force field (GFN‐FF, GAFF, MMFF94) and standard semiempirical methods (PM3, AM1, RM1, PM6, PM6‐D3, PM6‐D3H4, PM7) can reproduce reference RI‐SCS‐MP2 conformational energies. Tight‐binding GFNn‐xTB methods provide more realistic conformational energies which are accurate enough to discard the least stable conformers. The effect of thermodynamic correction is moderate and can be ignored if the gas phase conformational stability ranking is a goal. The influence of continuum solvation is stronger, especially if reinforced with the Gibbs free energy thermodynamic correction, and results in the reduced spread of conformational energies. The cluster formation binding energies strongly depend on a particular approach to vibrational thermochemistry with the difference between traditional harmonic and modified scaled rigid – harmonic oscillator approximations reaching 10 kcal mol−1. [ABSTRACT FROM AUTHOR]

This publication reports a facile and convenient preparation of tri-O-acetyl-glucopyranoses, derived from the corresponding 2-deoxyaminosugar, where the vicinal anomeric and C2 positions are decorated by azido and (thio)ureido groups, respectively. This double functionalization leads to an inherently chiral core incorporating the versatile azido and (thio)ureido linkages prone to further manipulation. The latter also provides a structural element for hydrogen-bonded donor-acceptor (HB-DA) sites, which are of immense value in organocatalytic pursuits. A computation-aided conformational analysis unveils the landscape of available conformers and their relative stability. N-aryl (thio)ureas bearing substituents at ortho positions exist as mixtures of M- and P-atropisomeric conformers. [ABSTRACT FROM AUTHOR]

Bile acid salts are steroid biosurfactants that build relatively small micelles compared to surfactants with an alkyl chain due to the rigid conformation of the steroid skeleton. In order to increase the capacity of micellar solubilization of the hydrophobic molecular guest, certain C7 alkyl derivatives were synthesized. Namely, introducing an alkyl group in the C7 position of the steroid skeleton results in a more effective increase in the micelle's hydrophobic domain (core) than the introduction in the C3 position. In comparison, fewer synthetic steps are required than if alkyl groups are introduced into the C12 position of cholic acid in the Grignard reaction. Here, the thermodynamic parameters of micellization (demicellization) of C7 alkyl (number of C atoms in the alkyl group: 2, 3, 4, and 8) derivatives of cholic acid anion in an aqueous solution without additives are examined (which have not yet been determined) in the temperature interval T (10–40) °C. The critical micellar concentration and the change in the standard molar enthalpy of demicellization ( ∆ h d e m i c 0 ) are determined by isothermal calorimetric titration (ICT). From the temperature dependence of ∆ h d e m i c 0 , the change in the standard molar heat capacity of demicellization is obtained ( ∆ C d e m i c 0 ), the value of which is proportional to the hydrophobic surface of the monomer, which in the micellar state is protected from hydrophobic hydration. The values of ∆ C d e m i c 0 indicate that in the case of C7-alkyl derivatives of cholic acid anion with butyl and octyl chains, parts of the steroid skeleton and alkyl chain remain shielded from hydration after disintegration of the micelle. Conformational analysis can show that starting from the C7 butyl chain in the alkyl chain, sequences with gauche conformation are also possible without the formation of steric repulsive strain between the alkyl chain and the steroid skeleton so that the C7 alkyl chain takes an orientation above the convex surface of the steroid skeleton instead of an elongated conformation toward the aqueous solution. This is a significant observation, namely, if the micelle is used as a carrier of a hydrophobic drug and after the breakdown of the micelle in the biological system, the released drug has a lower tendency to associate with the monomer if its hydrophobic surface is smaller, i.e., the alkyl chain is oriented towards the angular methyl groups of the steroid skeleton (the ideal monomer increases the hydrophobic domain of the micelle, but in aqueous solution, it adopts a conformation with the as small hydrophobic surface as possible oriented towards the aqueous solution)—which then does not disturb the passage of the drug through the cell membrane. [ABSTRACT FROM AUTHOR]

Ketene 1,3‐oxazoles and their derivatives present intriguing structures for the study of rotational barriers due to their pseudo–double‐bond character stemming from resonance in the ketene moiety. A diverse range of compounds featuring this motif underwent quantum‐chemical investigation to elucidate the nature of the stereochemical singularity observed in numerous cases. Because rotational barriers in most instances are too high to permit rapid interconversion, the findings are ascribed to thermodynamic rather than kinetic factors in the gas phase and within an implicit polar medium. The stabilities are attributed to internal hydrogen bonding where feasible. However, in cases where this is not possible, chalcogen bonding rather than steric effects governs the stereochemical preferences, particularly when S and Se comprise the heterocycle of these compounds. These findings hold promise for guiding the design of compounds whose properties hinge on stereochemistry and resonant structures, such as dyes. [ABSTRACT FROM AUTHOR]

A memorial tribute detailing the life and scientific accomplishments of Frank A. L. Anet, a pioneer of nuclear magnetic resonance (NMR) spectroscopy who discovered bedrock principles in organic chemistry and magnetic resonance. He was the first to show that nuclear Overhauser effects could provide structural information, significantly impacting future NMR applications. In the 1960s and 1970s, he built entire multinuclear NMR spectrometers operating as high as 396 MHz for protons, detecting nuclei inaccessible to commercial instruments, and operating at very low temperatures for studying molecular structure and dynamics. A titan of physical organic chemistry, Frank made important contributions in the areas of conformational analysis, stereochemistry, isotope effects, NMR relaxation theory, and chemical origins of life. [ABSTRACT FROM AUTHOR]

Measurement of scalar couplings between protons is a very challenging task because of complex multiplet patterns and severe overlapping of these multiplets in congested 1D spectra. Numerous 2D J‐resolved sequences now exist that utilize either the Zangger‐Sterk or PSYCHE or z‐filter elements along with selective refocusing and pure‐shift schemes to generate high‐resolution phase‐sensitive spectra with simple doublets in F1$$ {F}_1 $$ dimension. Herein, we present a 2D J‐resolved sequence that employs a simple element consisting of hard pulses and inter‐pulse delays to generate phase‐sensitive spectra. This simple element in combination with selective refocusing eliminates all the undesired components including the intense axial peaks, thus provides clean 2D J‐resolved spectra with signals of only two targeted protons with simple doublets in F1$$ {F}_1 $$ dimension and full multiplets of target protons in F2$$ {F}_2 $$ dimension. This high selectivity thus obviates the need for extra filtering elements and pure‐shift acquisition schemes that are integrated into existing sequences to facilitate coupling measurements in overcrowded signals. It is therefore anticipated that this sequence, with the ease of implementation and ability to extract coupling values from highly congested spectra, should turn out an important tool for structural and conformational analyses in chemical and biological studies. [ABSTRACT FROM AUTHOR]

In the present study, conformations and aromaticity of seventeen [13], [23] and [33] double-stranded cyclophanes composed of three benzene moieties were investigated at B3LYP level of density functional theory. The stability of these conformers is different depending on the type of cycloalkane-like cycles formed by (CH2) n bridges and the peripheral benzene rings, and also the curvature of the latter. In [13] cyclophane, this leads to only one conformer containing puckered cyclobutane-like cycle, at an angle of about 37◦. In comparison, in cyclophanes [23] and [33], the corresponding cycles are cyclohexane-like and cyclooctane-like, respectively. While conformer 2a having TB-like cycles is the most stable member of the [23] family, of eight ground-state conformers obtained for [33], 3a with two Chair-Chair-like and one Twist-Chair-like cycles is the most stable one, and 3h with three Twist-Boat-like cycles being 6.5 kcal higher in energy than the former is the least stable member of series. In addition to the conformational analysis, the aromaticity of the series has been assessed using different indexes, including magnetic criteria nucleus-independent chemical shifts (NICS-based) at the cage and at the ring centers, HNMR chemical shift, Magnetic Susceptibility, HOMA and relative energy (RE). [ABSTRACT FROM AUTHOR]

While biological machines are powered mainly by chemical transformations, chemically driven artificial rotary motor systems are very limited. Here, we report an aniline‐phenol‐based rotary molecular motor that operates via an information ratchet mechanism. The 360° directional rotation about a single covalent bond can be chemically driven by reversible oxazepine formation. Both the oxazepine formation and hydrolysis steps are kinetically gated via dynamic kinetic resolution, arising from the kinetic bias of chiral catalysts for enantiomers. Given the 95 % ee (97.5 : 2.5) and 88 % ee (94 : 6) of the individual gating steps of motor analogues, the overall directionality ratio could be calculated to be 91.7 : 8.3 (97.5 %×94 %≈91.7 %), which means that the motor will make one mistake (backward rotation) approximately every 11 to 12 turns. [ABSTRACT FROM AUTHOR]

Multidrug‐resistant (MDR) pathogens such as Escherichia coli, Pseudomonas aeruginosa, and Enterobacter cloacae have become a global health threat. Drug repositioning or repurposing has become a viable solution to combat the threat posed by MDR pathogens. A strategic approach to identifying potential new candidates as future molecular drug targets is presented in this study. Fifty proteins critical for virulence during systemic infection were selected from the entire genomes of MDR E. coli MB641 and Enterobacter cloacae MB649, which were isolated from infected orthopaedic implants. Interaction networks were built using the STRING database to visualise the positioning of the selected virulence proteins in the network space and support their suitability for therapeutic targeting. The two significant virulence proteins FliG and FlhA, which were discovered by network analysis, were suggested as prospective treatment targets. To test the stability of the protein–drug complexes, the preidentified proteins were docked with 10 marketed antibacterial drugs and six phytochemicals. Amikacin, rifampicin, streptomycin, and tetracycline had the best binding interaction and stability for both strains, according to our findings. Molecular dynamic simulation studies were performed for amikacin and catechin at 100 ns. Both hydrophobic and hydrophilic stable contacts were seen in the active sites of amikacin and catechin with new chemical structures. Structural and conformational analysis of the docked protein‐ligand complex was done by RMSD which showed stability of the amikacin and catechin complexes, whereas RMSF showed conformational changes. Based on the results, we propose the phytochemical catechin as the best theoretical lead, which may be further experimentally studied for selective inhibition. [ABSTRACT FROM AUTHOR]

Glucose abnormality is one of the atypical symptoms mostly overlooked during severe malaria. Screening for proteases involved in glucose abnormality suggests a potential new drug target. PF11_0189 is a putative insulin degrading enzyme found in the genome of Plasmodium falciparum. In silico approach revealed that PF11_0189 is similar to the metalloproteases exhibiting a zinc binding motif. The substrate binding region of PF11_0189 catalytic domain is lined by residues of a mixed nature, enabling the accommodation of both hydrophobic and hydrophilic residues from substrates. Analysis of each amino acid position from combinatorial peptide library suggests Thr and Ser to be the most crucial residues as upon its mutation significant improvement is observed in the binding. The peptides P‐21 (VPICSLY), P‐70 (TMICVLY), and P‐121 (AVICSLY) demonstrate significantly better interaction within the active site than a template peptide (TSICSLY). Molecular dynamic simulations confirm the complex's integrity, with all structures within the qualitative limit of compactness and stability during the simulation time. Principal component analysis (PCA) reveals major conformational motions and different energy landscapes, while dynamic cross‐correlation matrix (DCCM) highlights residue interactions of the complexes. The insights obtained through computational methods provide clues about substrate selectivity in PF11_0189, which can be utilized for peptide‐based therapeutics against severe malaria. [ABSTRACT FROM AUTHOR]

Ion mobility‐mass spectrometry (IM‐MS) has recently contributed to the structural analysis of molecules, including supramolecules and proteins, by determining the ion arrival time distributions correlated with the collision cross sections (CCSs), as well as the mass‐to‐charge ratios. However, its application range is still limited owing to the lack of general CCSs simulation methods based on possible molecular conformations. Here, a molecular dynamics‐based conformational search method for simulating CCS distributions using projection approximation is reported. As a case study, the gas‐phase conformations of the sodium adducts of conformationally flexible polyketones with 3,3‐dimethylpentane‐2,4‐dione as the monomer are analyzed. The sodium adduct of the hexamer (m/z 781.4 for [1 + Na]+) showed a monomodal arrival time distribution, but that of the octamer sodium adduct (m/z 1033.5 for [2 + Na]+) is multimodal. The conformational analysis indicated an unimodal CCS distribution of simulated [1 + Na]+ conformations in which the sodium cation is mainly bound at the chain terminal. Conversely, four clusters of conformations are obtained for [2 + Na]+ based on the Na+‐coordination sites, which qualitatively reproduced the observed CCS distribution. This approach will extend the utility of IM‐MS for the conformational analysis of flexible molecules in the gas phase. [ABSTRACT FROM AUTHOR]

The conformational possibilities of the casoxin D (Tyr1-Val2-Pro3-Phe4-Pro5-Pro6-Phe7) molecule were studied by theoretical conformational analysis. The potential function of the system is chosen as the sum of non-valence, electrostatic and torsion interactions and the energy of hydrogen bonds. The low-energy conformations of the casoxin D molecule, the dihedral angles of the main and side chains of the amino acid residues that make up the molecule were found, and the energy of intra- and interresidual interactions was estimated. It has been shown that the spatial structure of the casoxin D molecule is represented by conformations of eight shapes of the peptide skeleton. The results obtained can be used to elucidate the structural and structural-functional organisation of casoxin molecules. [ABSTRACT FROM AUTHOR]

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We describe the synthesis and computational investigation of N‐heterocycle‐substituted hexa‐peri‐hexabenzocoronenes (HBCs). Following our method for the preparation of thioether‐substituted HBCs, we prepared pyrrole‐, indole‐, carbazole‐, and 1H‐benz[g]indole‐substituted HBCs from the corresponding fluorinated precursors under microwave irradiation. A series of polysubstituted benzoindole‐HBCs with windmill architectures was also synthesized using the polyfluorinated HBC analogs, and the substituent effects on the electronic properties of the HBC core were investigated. Similar to the thioether substituted HBCs, the nature of the heterocycle does not influence the optoelectronic properties of the HBC core. The attachment of multiple benzoindole substituents leads to a bathochromic shift of the absorption and emission spectra, comparable to our previous studies. Due to the circular arrangement of the benzoindole moiety, the attachment of multiple substituents results in the presence of multiple conformers at room temperature. The rotation barrier can be overcome by heating the compounds to 323–333 K. Additionally, the investigation of the relaxed geometries shows two π‐stacking motifs within the conformers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A novel polymorph of an immunosuppressant drug azathioprine (AZP) is prepared (F-III) along with two solvates (2-methoxyethanol (MEE) and 1,4-dioxane (DOX)) and a monohydrate of AZP. The crystal structures were determined and further characterized by powder XRD and thermal and spectroscopy analysis. So far two polymorphs of AZP have been reported in the literature with crystal structure details, namely F-I and F-II. The novel polymorph F-III crystallizes in the monoclinic crystal system with the centrosymmetric P21/c space group. AZP F-III crystallizes serendipitously during cocrystallization experiments using DL -malic acid as a coformer. The single-crystal data showed distinct cell lengths and cell angles to confirm the novel polymorph of AZP. The conformational analysis of the novel polymorph shows unique torsion angles as compared to reported forms, demonstrating the conformational polymorphic form of AZP. The thermal analysis data revealed a lower melting point of F-III compared to that of F-I and both the forms decompose upon melting. The solubility results in different buffer media revealed that F-III exhibits a slightly higher solubility than F-I; the dissolution profile of F-III displayed a similar drug release in acidic, phosphate and purified water media. The polymorph stability under accelerated conditions showed the instability of F-III under accelerated humidity conditions (90–95% RH, 40 °C). Further, F-III exhibited solvent-dependent stability at room temperature. Finally, a process for developing F-III is established on a lab scale by a simple recrystallization method in a combination of solvents. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ecklonia maxima is an endemic South African seaweed with numerous commercially valuable compounds, including sodium alginate. This polysaccharide contains 1,4-linked β-d-mannuronic (M) and α-l-guluronic acid (G) residues, and has enormous health and food applications and benefits for biomedicine. In this study, acid extraction of sodium alginate from Ecklonia maxima was performed, and its chemical and physical properties were compared with commercial sodium alginate. A yield of 58.7 % (w/w of dry alga) sodium alginate was recovered from the seaweed. As expected, Fourier-transform infrared spectroscopy and nuclear magnetic resonance spectroscopic analyses of sodium alginate revealed the presence of M and G residues in the polysaccharide. Circular dichroism (CD) spectroscopy revealed an M/G ratio of 1.86 from the extracted sodium alginate. The viscosity average molecular weight of sodium alginate was 429 kDa using the Mark–Houwink–Sakurada equation. Three-dimensional conformational analysis by Congo red and CD spectroscopy suggested that sodium alginate exhibits a triple-helix conformation in solution. Furthermore, X-ray powder diffraction analysis confirmed that the alginate has an amorphous structure. Sodium alginate extracted from E. maxima found on the coasts of Southern Africa exhibits a high mannuronic content and high viscosity, potentially beneficial for drug delivery and biomedical applications. [ABSTRACT FROM AUTHOR]

A series of N-alkylfuran-2-carboxamide derivatives was easily prepared through direct acylation of diverse amines with 2-furoyl chloride. Using an E. coli reporter strain, all compounds were then examined as LuxR-regulated quorum sensing modulators for their agonistic or antagonistic activity. Compounds with a C8 or specially C6 alkyl chain with a comparable chain length with the natural ligand of LuxR were found to be antagonists with an IC50 value of 25 µM. Competition experiments between the N-hexylfuran-2-carboxamide with the natural ligand indicate that the LuxR activity could be restored with high concentration of LuxR ligand. Conformational analysis, docking simulations and protein-ligand affinity prediction suggest that furan-2-carboxamide derivatives interact within the LuxR binding site via H-bonds of the C = O oxygen atom with Tyr62 OH and of the amide NH with Asp79 carboxylate, Tyr62 and Asp79 being two important conserved residues in the LuxR family. The binding mode also suggests that the absence of the hydrogen bond with Trp66, normally observed for the amide retroisoster analogs having the lactone instead of the furyl moiety, is not deleterious to the ability to interact and induce inhibition. [ABSTRACT FROM AUTHOR]

Unlike their planar counterparts, classic synthetic protocols for C–C bond forming reactions on nonplanar porphyrins are underdeveloped. The development of C–C bond forming reactions on nonplanar porphyrins is critical in advancing this field of study for more complex porphyrin architectures, which could be used in supramolecular assemblies, catalysis, or sensing. In this work a library of arm-extended dodecasubstituted porphyrins was synthesized through the optimization of the classic Suzuki–Miyaura coupling of peripheral haloaryl substituents with a range of boronic acids. We report on palladium-catalyzed coupling attempts on the ortho-, meta-, and para-meso-phenyl position of sterically demanding dodecasubstituted saddle-shaped porphyrins. While para- and meta-substitutions could be achieved, ortho-functionalization in these systems remains elusive. Furthermore, borylation of a dodecasubstituted porphyrin’s meso-phenyl position was explored and a subsequent C–C coupling showed the polarity of the reaction can be reversed resulting in higher yields. X-ray analysis of the target compounds revealed the formation of supramolecular assemblies, capable of accommodating substrates in their void.

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. [ABSTRACT FROM AUTHOR]

Iron is an essential nutrient for maintaining red blood cell metabolism and assisting bone marrow hematopoiesis. Iron deficiency can cause various diseases, such as anemia, stunted growth, and premature birth in pregnant women. As a new iron supplement product, peptide iron chelate has been used as a new ideal iron supplement in recent years because of its advantages of high absorption rate, safety, and no side effects. This paper mainly reviews the preparation of foodborne peptides and peptide iron chelates and the factors affecting their chelation activity, explored the iron-binding mechanism of peptides, summarizes their binding sites and chelation patterns, further analyzes their conformational changes and intermolecular forces, and summarizes how they promote iron bioavailability. The aim is to provide a reference for developing and applying iron peptide chelates in functional foods and new iron supplements.

Acetal substitution reactions can proceed by a number of mechanisms, but oxocarbenium ion intermediates are involved in many of these reactions. Our research has focused on understanding the conformational preferences, structures, and reactions of these intermediates. This account summarizes our observations that electrostatic effects play a significant role in defining the preferred conformations, and that torsional effects determine how those intermediates react. Neighboring-group effects are not as straightforward as they might seem, considering that oxocarbenium ion intermediates are in equilibrium with structures that involve stabilization by a nearby substituent. 1 Introduction 2 Unexpected Stereoselectivities 3 Determining Conformational Preferences of Oxocarbenium Ions 4 Structures of Carbocations by NMR Spectroscopy and X-ray Crystallography 5 Stereoelectronic Models for Reactions Involving Other Oxocarbenium Ions 6 Stereoselectivity and Reactivity: When They Correlate, When They Do Not 7 Neighboring–Group Participation Is Not as Simple as It Seems 8 What Is True for Carbocations Is True for Carbonyl Compounds 9 Stereoelectronic and Torsional Effects in Reactions of Enolates 10 Summary of Expected Selectivities for Reactions of Cyclic Acetals 11 Conclusion [ABSTRACT FROM AUTHOR]

A profound understanding of the binding dynamics of drugs with plasma proteins is highly important as it determines its therapeutical potential. Herein, we have investigated the molecular interaction of Tucatinib (TUC), a novel, primitive and highly selective drug for treatment of HER2+ advanced unresectable breast cancer, with bovine serum albumin (BSA) using multi‐pronged spectroscopic techniques and molecular docking. TUC considerably quenched the intrinsic fluorescence of BSA via static quenching mechanism, and it binds to the hydrophobic cleft of subdomain IIA of BSA with a moderate binding affinity. The thermodynamic analysis revealed the major interplay of van der Waals forces and hydrogen bonding interactions in stabilising the binding. The Förster distance 'r' signifies feasible energy transfer between BSA and TUC. The conformational analyses indicate some alterations in the protein secondary structure as a consequence of some changes in the protein polar environment due to complex formation. The experimental results are supported by docking analyses. [ABSTRACT FROM AUTHOR]

Multiscale structural evolution of conjugated polymer (CP) solutions from disorder to aggregation via environmental perturbations is a universal phenomenon in condensed matter physics. Here, we take poly(3‐hexylthiophene‐2,5‐diyl) (P3HT) as a model material and use Ultraviolet–Visible (UV–Vis) spectroscopy to study the hierarchical structure evolution during prolonged aging at relatively low temperature. Using in‐situ UV–Vis spectroscopy and the Franck‐Condon (FC) method, the dynamics of multiscale structural transitions in P3HT were elucidated. Hierarchical structural details can be extracted from the UV–Vis spectra, including the overall percentage of aggregates, conjugation length, degree of H‐/J‐type molecular packing, and site energetic disorder. Through covariance analysis of conformational disorder to aggregation transitions of conjugated polymers obtained under multiple conditions, we find that the trends of the above four key parameters are not consistent, which informs the unique evolution of the degree of ordering at different length scales within the aggregates. This work facilitates the scrutiny of the hierarchical structural transition from multi‐length scale perspective. [ABSTRACT FROM AUTHOR]

α,β‐Dichlorocarbonyl compounds were synthesized by facile dichlorination of α,β‐unsaturated amides with TCIA‐PPh3 and the resultant amides were converted to ketones. Conformational analyses of the products were performed to confirm our previous hypothesis regarding vicinal dichlorinated carbonyl compounds. The compounds exhibited 1H NMR signals with large coupling constants (7–11 Hz) for the 1,2‐anti‐configuration and small coupling constants (3–4 Hz) for the 1,2‐syn‐configuration. The syn‐pentane interaction enabled rational conformational analysis of the α,β‐dichlorinated carbonyl compounds, although some interesting exceptions were observed. Consideration of these conformations is helpful in assigning relative configurations of α,β‐dihalogenated carbonyl compounds in general. [ABSTRACT FROM AUTHOR]

The production of androst-4-ene-3,17-dione (AD) by the steroidal microbial cell factory requires transcription factors (TFs) to participate in metabolic regulation. However, microbial cell factory lacks effective TFs that can respond to AD in its metabolic pathway. Additionally, finding and obtaining natural TFs that specifically respond to AD is a complex and onerous task. In this study, we devised an artificial TF that responds to AD, termed AdT, based on structure-guided molecular dynamics (MD) simulation. According to MD analysis of the conformational changes of AdT after binding to AD, an LBD in which the N- and C-termini exhibited convergence tendencies was used as a microswitch to guide the assembly of a DNA-binding domain lexA, a linker (GGGGS)2, and a transcription activation domain B42 into an artificial TF. As a proof of design, a AD biosensor was designed and constructed in yeast on the basis of the ligand-binding domain (LBD) of hormone receptor. In addition, the transcription factor activity of AdT was increased by 1.44-fold for its variant F320Y. Overall, we created non natural TF elements for AD microbial cell factory, and expected that the design TF strategy will be applied to running in parallel to the signaling machinery of the host cell. [ABSTRACT FROM AUTHOR]

We recently introduced calix[n]naphth[m]arenes as a novel class of deep-cavity hybrid macrocycles constituted by phenol (n) and naphthalene (m) units. In this study, we report the synthesis, conformational analysis, spectroscopic properties, and solid-state structures of calix[4]naphth[4]arene (C4N4) and its permethylated analog (C4N4-Me), thereby expanding the calix[n]naphth[m]arene family. C4N4 was synthesized through a 2 + 2 fragment coupling macrocyclization under acidic conditions, where the solvent played a crucial role in selectively forming the C4N4 derivative. The X-ray structure of C4N4 reveals a chair-like 1,2,3,4-alternate conformation characterized by two opposing 3/4-cone moieties stabilized by intramolecular hydrogen bonds. In contrast, the X-ray structure of C4N4-Me exhibits a 1,3,5,7-alternate conformation. [ABSTRACT FROM AUTHOR]

Several proteins from plant pathogenesis‐related family 10 (PR10) are highly abundant in the latex of opium poppy and have recently been shown to play diverse and important roles in the biosynthesis of benzylisoquinoline alkaloids (BIAs). The recent determination of the first crystal structures of PR10‐10 showed how large conformational changes in a surface loop and adjacent β‐strand are coupled to the binding of BIA compounds to the central hydrophobic binding pocket. A more detailed analysis of these conformational changes is now reported to further clarify how ligand binding is coupled to the formation and cleavage of an intermolecular disulfide bond that is only sterically allowed when the BIA binding pocket is empty. To decouple ligand binding from disulfide‐bond formation, each of the two highly conserved cysteine residues (Cys59 and Cys155) in PR10‐10 was replaced with serine using site‐directed mutagenesis. Crystal structures of the Cys59Ser mutant were determined in the presence of papaverine and in the absence of exogenous BIA compounds. A crystal structure of the Cys155Ser mutant was also determined in the absence of exogenous BIA compounds. All three of these crystal structures reveal conformations similar to that of wild‐type PR10‐10 with bound BIA compounds. In the absence of exogenous BIA compounds, the Cys59Ser and Cys155Ser mutants appear to bind an unidentified ligand or mixture of ligands that was presumably introduced during expression of the proteins in Escherichia coli. The analysis of conformational changes triggered by the binding of BIA compounds suggests a molecular mechanism coupling ligand binding to the disruption of an intermolecular disulfide bond. This mechanism may be involved in the regulation of biosynthetic reactions in plants and possibly other organisms. [ABSTRACT FROM AUTHOR]

Cervical malignancy (CC) is the 2nd most prevalent malignancy among females, leading to cancer mortality. Primary detection of CC tumors results in an improved prognosis. CC is a malignant gynecological tumor, with few treatment options. New diagnostic and therapeutic agents are required to expand patient survival and quality of life. If CC tumors can be found at an early stage, the prognosis is much brighter. New diagnostic and therapeutic agents are needed to increase patient survival and quality of life. In this work, we performed whole-exome sequencing utilizing V5 (Illumina platform) 10 samples, 5 control and 5 CC tumour tissue, and we compared the results with transcriptome studies. KMT2C variations were shown to be among the most vicious in this analysis. From an Indian viewpoint, we found a plethora of SNVs and mutations, including those with known, unknown, and possible effects on health. Based on our findings, we know that the KMT2C gene is on chr. Seven and in exon 8, all three recognized variants are missense, synonymous, coding synonymous, non-coding variants, and GnomAD MAF (− 0.05). The variation at position (7:152265091, T > A, SNV 62478356) in KMT2C is unique, potent, and pathogenic. The missense coding transcript CIQTNF maps to chromosome 7 and displays T > C SNV. In addition, we performed single strand conformational polymorphism analysis on 64 samples and further confirmed them using Sanger sequencing to understand and verify the mutations. KMT2C shows a log FC value of − 1.16. Understanding emerging harmful mutations from an Indian viewpoint is facilitated by our bioinformatics-based, extensive correlation studies of WES analysis. Potentially harmful and new mutations were found in our preliminary analysis; among these ten top mutated genes, KMT2C and CIQTNF were altered in ten cases of CC with an Indian phenotype. [ABSTRACT FROM AUTHOR]

Translocator protein (TSPO) is an 18 kDa transmembrane protein, localized primarily on the outer mitochondrial membrane. It has been found to be involved in various physiological processes and pathophysiological conditions. Though studies on its structure have been performed only recently, there is little information on the nature of dynamics and doubts about some structures referenced in the literature, especially the NMR structure of mouse TSPO. In the present work, we thoroughly study the dynamics of mouse TSPO protein by means of atomistic molecular dynamics simulations, in presence as well as in absence of the diagnostic ligand PKA. We considered two starting structures: the NMR structure and a homology model (HM) generated on the basis of X-ray structures from bacterial TSPO. We examine the conformational landscape in both the modes for both starting points, in presence and absence of the ligand, in order to measure its impact for both structures. The analysis highlights high flexibility of the protein globally, but NMR simulations show a surprisingly flexibility even in the presence of the ligand. Interestingly, this is not the case for HM calculations, to the point that the ligand seems not so stable as in the NMR system and an unbinding event process is partially sampled. All those results tend to show that the NMR structure of mTSPO seems not deficient but is just in another portion of the global conformation space of TSPO. • Mouse TSPO is a highly dynamic structure. • Despite similar helical contents, conformations show various side chain TM contacts. • TSPO remains highly flexible even bound to the PK-11195 ligand. • Both TSPO and ligands are mutually adaptative to each other for efficient binding. • This mutual adaptation is totally relevant with the diversity of TSPO ligands. [ABSTRACT FROM AUTHOR]

To better understand the molecular genetics of the Shiga toxin type 2 subunit A gene (stx2A gene), we collected many subtypes of stx2A genes and performed detailed molecular evolutionary analyses of the gene. To achieve the aim of the study, we used several bioinformatics technologies, including time-scaled phylogenetic analyses, phylogenetic distance analyses, phylodynamics analyses, selective pressure analyses, and conformational epitope analyses. A time-scaled phylogeny showed that the common ancestor of the stx2A gene dated back to around 18,600 years ago. After that, the gene diverged into two major lineages (Lineage 1 and 2). Lineage 1 comprised the stx2a–2d subtypes, while Lineage 2 comprised the stx2e, 2g, 2h, and 2o subtypes. The evolutionary rates of the genes were relatively fast. Phylogenetic distances showed that the Lineage 2 strains had a wider genetic divergence than Lineage 1. Phylodynamics also indicated that the population size of the stx2A gene increased after the 1930s and spread globally. Moreover, negative selection sites were identified in the Stx2A proteins, and these sites were diffusely distributed throughout the protein. Two negative selection sites were located adjacent to an active site of the common Stx2A protein. Many conformational epitopes were also estimated in these proteins, while no conformational epitope was found adjacent to the active site. The results suggest that the stx2A gene has uniquely evolved and diverged over an extremely long time, resulting in many subtypes. The dominance of the strains belonging to Lineage 1 suggests that differences in virulence may be involved in the prosperity of the offspring. Furthermore, some subtypes of Stx2A proteins may be able to induce effective neutralizing antibodies against the proteins in humans. [ABSTRACT FROM AUTHOR]

The influence of the solution environment on the solution crystallisation of the conformational polymorphic forms I and II of tolfenamic acid is assessed through integration of multi-scale (molecular, cluster and crystallographic) modelling with polymorphic screening using polythermal crystallisation as a function of solvent selection. Solid-state analysis reveals the contrasting crystal chemistry with the strongest synthon involving hydrogen bonding synthons and π–π van der Waals interactions for forms I and II, respectively. Analysis of the molecular conformational energies reveals molecular structures for forms I and II to be very close which is matched by their calculated lattice energies. Crystallisation as a function of both solute concentration and solution cooling rate reveals form II to be mostly more preferred than form I. The higher stability of the form II conformer together with its easier conformational adjustment during the formation of form II crystals, is consistent with its greater crystallisability compared to the more stable form I. Solute concentration analysis of the relative stabilities of the two forms as a function of their sizes reveals that smaller cluster sizes are required to stabilise the crystal structure for form I with respect to form II. Polymorphic screening as a function of solvent confirms the predicted poor crystallisability of form I whose crystallisation is preferred at higher initial solute concentrations and lower cooling rates in polar solvents but less so for the more apolar solvent toluene, the latter being consistent with π–π solute/solvent interactions promoting the formation of hydrogen bonded solute/solute synthons at the expense of π–π interactions. Modelling work correlates well with the observed crystallisation behaviour, highlighting the importance of understanding solvent selection and solution state structure at the molecular-scale level for directing polymorphic outcomes, as confirmed by the higher crystallisability of the metastable form II. [ABSTRACT FROM AUTHOR]

Compounds containing the thiophene moiety find several applications in physics and chemistry, such as electrical conduction, which depends on specific conformations to properly exhibiting the desired properties. In turn, chalcogen bonding has found to modulate the conformation of some N‐thiophen‐2‐ylfomamides. Since halogens participate in a kin interaction (halogen bonding) and are abundant in agrochemicals, pharmaceuticals, and materials, we have quantum‐chemically explored the interaction between organic halogen and thiophene as a conformational modulator in some model compounds. Although such interaction indeed appears, as demonstrated by atoms in molecules and natural bond orbital analysis, it is inefficient to control the conformational equilibrium. An energy decomposition analysis scheme demonstrated that halomethane and thiophene tend to move away from one another due to a core component (Pauli repulsion and exchange), which is mainly due to a deformation term. Therefore, chalcogen bonds with halogens appear weaker than with other chalcogens. [ABSTRACT FROM AUTHOR]

An effective method has been developed for the synthesis of unique macrohetero[N,S]cycles 1,4,7(8,9,10,11,12,14)-trithia-2,9(10,11,12,13,14,16)-diazacycloalkane 1,1-dioxides by cyclothiomethylation of sulfonamide with bishydroxydithioalkanes and 1,3,6(7)-oxadithioalkanes in the presence of rare earth metal catalysts. A detailed conformational analysis of 1,4,7-trithia-2,9-diazacycloalkane 1,1-dioxide has been carried out, and the energetically most probable path of cyclic interconversion has been proposed. [ABSTRACT FROM AUTHOR]

The conformational preferences of N‐((6‐methylpyridin‐2‐yl)carbamothioyl)benzamide were studied in solution, the gas phase and the solid state via a combination of NMR, density functional theory (DFT) and single crystal X‐ray techniques. This acyl thiourea derivative can adopt two classes of low energy conformation, each stabilized by a different 6‐membered intramolecular hydrogen bond (IHB) pseudoring. Analysis in different solvents revealed that the conformational preference of this molecule is polarity dependent, with increasingly polar environments yielding a higher proportion of the minor conformer containing an NH⋅⋅⋅N IHB. The calculated barrier to interconversion is consistent with dynamic behaviour at room temperature, despite the propensity of 6‐membered IHB pseudorings to be static. This work demonstrates that introducing competitive IHB pathways can render static IHBs more dynamic and that such systems could have potential as chameleons in drug design. [ABSTRACT FROM AUTHOR]

6‐Iodo‐3‐(triflamidomethyl)‐4‐triflyl‐1,4,2,7‐oxazadisilepane 1 and the product of its cyclization, 2,2,4,4‐tetramethyl‐6,8‐bis (triflyl)‐3‐oxa‐6,8‐diaza‐2,4‐disilabicyclo[3.2.2]nonane 2, have been studied by gas‐phase electron diffraction and DFT calculations. The conformational equilibrium in the gas phase was shown to include three and two conformers for 1 and 2, respectively, in contrast to only one conformer determined by single crystal X‐ray diffraction. The structural analysis of the conformers was performed and the pathways of the conformational transitions were analyzed. [ABSTRACT FROM AUTHOR]

The study presents a thorough and detailed analysis of bicalutamide's structural and conformational properties. Quantum chemical calculations were employed to explore the conformational properties of the molecule, identifying significant energy differences between conformers. Analysis revealed that hydrogen bonds stabilise the conformers, with notable variations in torsion angles. Conformers were classified into 'closed' and 'open' types based on the relative orientation of the cyclic fragments. NOE spectroscopy in different solvents (CDCl3 and DMSO-d6) was used to study the conformational preferences of the molecule. NOESY experiments provided the predominance of 'closed' conformers in non-polar solvents and a significant presence of 'open' conformers in polar solvents. The proportions of open conformers were 22.7 ± 3.7% in CDCl3 and 59.8 ± 6.2% in DMSO-d6, while closed conformers accounted for 77.3 ± 3.7% and 40.2 ± 6.2%, respectively. This comprehensive study underscores the solvent environment's impact on its structural behaviour. The findings significantly contribute to a deeper understanding of conformational dynamics, stimulating further exploration in drug development. [ABSTRACT FROM AUTHOR]

Intrinsically disordered protein α-synuclein (αS) is implicated in Parkinson's disease due to its aberrant aggregation propensity. In a bid to identify the traits of its aggregation, here we computationally simulate the multi-chain association process of αS in aqueous as well as under diverse environmental perturbations. In particular, the aggregation of αS in aqueous and varied environmental condition led to marked concentration differences within protein aggregates, resembling liquid-liquid phase separation (LLPS). Both saline and crowded settings enhanced the LLPS propensity. However, the surface tension of αS droplet responds differently to crowders (entropy-driven) and salt (enthalpy-driven). Conformational analysis reveals that the IDP chains would adopt extended conformations within aggregates and would maintain mutually perpendicular orientations to minimize inter-chain electrostatic repulsions. The droplet stability is found to stem from a diminished intra-chain interactions in the C-terminal regions of αS, fostering inter-chain residue-residue interactions. Intriguingly, a graph theory analysis identifies small-world-like networks within droplets across environmental conditions, suggesting the prevalence of a consensus interaction patterns among the chains. Together these findings suggest a delicate balance between molecular grammar and environment-dependent nuanced aggregation behavior of αS. [ABSTRACT FROM AUTHOR]

Simultaneous desulfurization and denitration by using activated coke is one of the most competitive technologies for cleaning low-temperature steel flue gases. The key to denitration performance relies on the regulation of active groups on the catalyst. In this work, the carboxyl and lactone groups with (NH4)2S2O8 oxidation and thermal treatment were found to mainly determined the catalytic activity. The results showed that (NH4)2S2O8-treated AC catalyst improved denitration activity at low temperatures, which was attributed to the increase in oxygen-containing groups of the AC, the thermal treatment enhanced the low-temperature activity while reduced the performance in (210–240 ℃). According to the characterization results and conformational relationship analysis, we revealed that the adsorption and activation of NH3 mainly depended on carboxyl groups during the middle-temperature range (210–240 ℃) NH3–SCR. Based on the advantage of middle-temperature denitration activity of modified activated coke, the carboxyl groups on activated coke were the most important active sites for the NH3–SCR reaction. Moreover, lactone groups, improved the denitration performance via promoting NO oxidation at low-temperatures range (120–150 ℃). However, the presence of only lactone groups in the 210–240 ℃ is not beneficial for the further promotion for denitration activity. This work initially reveals the decisive role of carboxyl and lactones groups of activated coke for the low-temperature NH3-SCR reaction, and guides the industrial arrangement of oxidation-modified AC as denitration catalyst. [ABSTRACT FROM AUTHOR]

This study aims to identify a cyanidin-3-rutinoside chloride that exhibits both photovoltaic performance and nonlinear optical properties, which may be utilized in the field of optoelectronics. Prior to investigating these properties, the stable structure must be determined. For this purpose, its conformational analysis is performed by the Molecular Force Field method with the spartan program. The exact nature of the stable configuration has been ascertained by empirical evidence. The energy of the stable configuration is -1654184.76 kcal/mol, and its dipole moment is 9.94 Debye. Cyanidin-3-rutinoside chloride has been investigated using experimental FT-IR and Raman spectroscopies. Meanwhile, the DFT method at the B3LYP/6-311 + + G(d, p) level was employed in order to study the simulated FT-IR and Raman spectra, the HOMO-LUMO analysis, the molecular electrostatic potentials (MEP), and the non-linear optical (NLO) characteristics of the title molecule. The HOMO and LUMO energies are − 6.45 and − 3.64 electron volts (eV), respectively, with a gap value of 2.81 eV. Additionally, the title compound's open-circuit voltage, the transition density matrix light-harvesting efficiency, driving force, and binding energy were calculated with by taking photovoltaic cell properties into account. Furthermore, investigations of hole reorganization energy, electron reorganization energy, and total reorganization energy were carried out at the B3LYP/6-31G(d, p) level for the cyanidin-3-rutinoside chloride of interest. In addition, density of state calculations and NBO were made at the B3LYP/6-31G(d, p) level. We calculated the following values for LHE, , , , , and : 0.06, 2.45 eV, 0.20 eV, 0.56 eV, 0.50 eV, 0.57 eV and 1.06 eV, respectively. [ABSTRACT FROM AUTHOR]

Introduction: The 13C-NMR data described for perezone (1), a 3-hydroxy p-quinone stated as the first natural product isolated as crystals in the New World, and rigidone (2), a 4-hydroxy o-quinone isolated from a coral species, are essentially the same. Some years ago, we described, using theoretical calculations, that a 4-hydroxy-1,2-quinone is more than 11 kcal/mol less stable than a 3-hydroxy-1,4-quinone making coexistence in nature of this type of quinones. In the present study, we approach the situation by comparing of the experimental 13C-NMR data for 1 and those described for 2 with the calculated using computational methods. Additional evidence was obtained from a X-ray diffraction analysis for the reaction product of perezone with o-phenylendiamine. Methods;The 13C-NMR data for the quinoid rings were calculated using the GIAO and CSGT methods, density functional theory (DFT) and the functional/basis set pairs B3LYP/6-31 g(d,p) and MPW1PW91/6-31 g(d,p); and TPSSTPSS/cc-PVTZ and PBE1PBE/aug-cc-PVDZ. Perezone reaction with o-phenylenediamine was achieved using a described method in MeOH at room temperature. X-Ray diffraction analysis of phenazine from perezone reaction was done using MoKα radiation. The data were used to calculate the Flack parameter. Results; After conformational analysis, complete optimization of the geometry of the conformers found and, calculation of the 13C-NMR chemical shifts for the quinone ring of 1 and 2, in all cases a better agreement was observed between the experimental data for 1 versus 2. Perezone reaction with o-phenylenediamine afforded the corresponding phenazine in its amine-keto tautomeric form as evidenced from a X-ray diffraction study. Conclusion; The better agreement observed between the experimental and calculated data for 1 versus 2, along with the free energy difference of more than 11 kcal/mol in favor of the 3-hydroxy p-quinone versus 4-hydroxy o-quinone, previously established for us, allow to say that the structure described for rigidone corresponds to ent -perezone. [ABSTRACT FROM AUTHOR]

The understanding of noncovalent interactions is crucial in explaining critical phenomena such as self‐assembly, chemical reactivity, and crystallization. This work examines the energetic diversity of conformations and local minima for several halogenated dimers, represented as R‐X (R = H, F, CH3, CF3; X = Cl, Br, I). Thousands of configurations are randomly generated and refined through geometric optimizations to yield a diverse set of molecular conformers. Frequency calculations were performed for all optimized conformers to confirm that they are local minima. The noncovalent interactions in optimized dimers of halogen‐containing molecules were analyzed with atom in molecules (AIM) method and symmetry‐adapted perturbation theory (SAPT). Additionally, a protocol for generating machine learning models to recover accurate predictions of the physically meaningful SAPT energy components with minor computational cost is presented. These results deepen our understanding of the intricate energy balance and dedicated equilibrium of different noncovalent interactions in halogenated dimers. [ABSTRACT FROM AUTHOR]

The cluster of four skipped exo‐methylene substituents on the "northern" wing of limaol renders this dinoflagellate‐derived marine natural product unique in structural terms. This arguably non‐thermodynamic array gains kinetic stability by virtue of populating local conformations which impede isomerization to a partly or fully conjugated polyene. This analysis suggested that the difficulties encountered during the late stages of our first total synthesis of this polyketide had not been caused by an overly fragile character of this unusual substructure; rather, an unfavorable steric microenvironment about the spirotricyclic core was identified as the likely cause. To remedy the issue, the protecting groups on this central fragment were changed; in effect, this amendment allowed all strategic and practical problems to be addressed. As a result, the overall yield over the longest linear sequence was multiplied by a factor of almost five and the material throughput increased more than eighty‐fold per run. Key‐to‐success was a gold‐catalyzed spirocyclization reaction; the reasons why a Brønsted acid cocatalyst is needed and the origin of the excellent levels of selectivity were delineated. The change of the protecting groups also allowed for much improved fragment coupling processes; most notably, the sequence of a substrate‐controlled carbonyl addition reaction followed by Mitsunobu inversion that had originally been necessary to affix the southern tail to the core could be replaced by a reagent controlled asymmetric allylation. Finally, a much‐improved route to the "northern" sector was established by leveraging the power of asymmetric hydrogenation of a 2‐pyrone derivative. Limaol was found to combine appreciable antiparasitic activity with very modest cytotoxicity. [ABSTRACT FROM AUTHOR]

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A series of 21 sulfoester and sulfonamide derivatives comprising two aromatic rings was synthesized to investigate the effect of the presence of either electron-donating (ED) or electron-withdrawing (EW) groups on the intramolecular π-stacking assembly. The positioning of ED or EW moieties was carried out directly on one of the aromatic rings linked to the sulfonyl or sulfonamide moieties. In contrast, the other aromatic ring (phenyl or pyridine) was connected by a –CH2–CH2– spacer with the sulfonyl or sulfonamide moiety. The purpose of having an ethyl spacer between the two aromatic rings was to achieve conformational flexibility, facilitating the intramolecular π-stacking assembly between the two aromatic rings. The use of sulfoester/sulfonamide groups allowed more conformational flexibility to attain desired orientations in solids with the interplay of the hydrogen-bonding interactions. Between the two functional groups, sulfonamides offered a more hydrogen-rich environment due to the amine moiety and may exhibit higher H-bonding propensity than the sulfoester moiety. The central idea here was to study the interplay between the hydrogen-bonding and π⋯π interactions. The substituent groups chosen were categorized as strong electron-withdrawing (–CF3 and –CN), weak electron-withdrawing (–Cl and –Br), neutral (–H), and good electron-donating (–CH3 and –OCH3) groups. Crystal structure analysis revealed the syn conformation for all the derivatives, enabling intramolecular π⋯π interactions between the two aromatic rings, whereas in the sulfonamide derivatives, the molecule takes either midway or anti conformations, except for one pyridine sulfonamide derivative, which showed the syn orientation but lacked intramolecular π-stacking interactions. The absence of any conventional H-bond forming functional groups in the sulfoester derivatives may have resulted in the syn geometry facilitated by intramolecular π-stacking interactions. Conversely, H-bond-forming functional groups in the sulfonamide derivatives could have prevented the syn conformation. The conformational analysis carried out employing density functional theory (DFT) calculations confirmed the higher stability of the syn conformation over the midway and anti orientations. [ABSTRACT FROM AUTHOR]

Proteins play a central role in biological processes, and understanding their conformational variability is crucial for unraveling their functional mechanisms. Recent advancements in high-throughput technologies have enhanced our knowledge of protein structures, yet predicting their multiple conformational states and motions remains challenging. This study introduces Dimensionality Analysis for protein Conformational Exploration (DANCE) for a systematic and comprehensive description of protein families conformational variability. DANCE accommodates both experimental and predicted structures. It is suitable for analysing anything from single proteins to superfamilies. Employing it, we clustered all experimentally resolved protein structures available in the Protein Data Bank into conformational collections and characterized them as sets of linear motions. The resource facilitates access and exploitation of the multiple states adopted by a protein and its homologs. Beyond descriptive analysis, we assessed classical dimensionality reduction techniques for sampling unseen states on a representative benchmark. This work improves our understanding of how proteins deform to perform their functions and opens ways to a standardised evaluation of methods designed to sample and generate protein conformations. [ABSTRACT FROM AUTHOR]

Unsaturated cyclic terpenes often exhibit instability due to the proximation of C=C bonds in the cyclic skeleton, leading to nonenzymatic degradation. In this study, the crystalline sponge (CS) method was employed for the X‐ray conformational analysis of a minute amount of oily and cyclic terpene compound, (+)‐germacrene D‐4‐ol, which was produced by a terpene synthase OILTS under in vitro conditions. The CS method revealed a reactive conformation of the cyclic terpene with proximal double bonds. Under weakly acidic in vivo conditions, OILTS gave four pseudo‐natural products or artifacts. The CS method also elucidated the structures of these degraded compounds, proposing a degradation mechanism triggered by the transannular reactions. [ABSTRACT FROM AUTHOR]

While peptide macrocycles with rigidified conformations have proven to be useful in the design of chemical probes of protein targets, conformational flexibility and rapid interconversion can be equally vital for biological activity and favorable physicochemical properties. This study introduces the concept of "structural pin", which describes a hydrogen bond that is largely responsible for stabilizing the entire macrocycle backbone conformation. Structural analysis of macrocycles using nuclear magnetic resonance (NMR), molecular modelling and X‐ray diffraction indicates that disruption of the structural pin can drastically influence the conformation of the entire ring, resulting in novel states with increased flexibility. This finding provides a new tool to interrogate dynamic behaviour of macrocycles. Identification of structural pins offers a useful conceptual framework to understand positions that can either be modified to give flexible structures or retained to maintain the rigidity of the scaffold. [ABSTRACT FROM AUTHOR]