All-trans Conformation Research Articles

Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides.

Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.

Taming Conformational Heterogeneity on Ion Racetrack to Unveil Principles that Drive Membrane Permeation of Cyclosporines.

Our study reveals the underlying principles governing the passive membrane permeability in three large N-methylated macrocyclic peptides (N-MeMPs): cyclosporine A (CycA), Alisporivir (ALI), and cyclosporine H (CycH). We determine a series of conformers required for robust passive membrane diffusion and those relevant to other functions, such as binding to protein targets or intermediates, in the presence of solvent additives. We investigate the conformational interconversions and establish correlations with the membrane permeability. Nuclear magnetic resonance (NMR) and cyclic ion-mobility spectrometry-mass spectrometry (cIMS-MS) are employed to characterize conformational heterogeneity and identify cis-amides relevant for good membrane permeability. In addition, ion mobility selected cIMS-MS and infrared (IR) multiple-photon dissociation (IRMPD) spectroscopy experiments are conducted to evaluate the energy barriers between conformations. We observe that CycA and ALI, both cyclosporines with favorable membrane permeabilities, display multiple stable and well-defined conformers. In contrast, CycH, an epimer of CycA with limited permeability, exhibits fewer and fewer stable conformers. We demonstrate the essential role of the conformational shift from the aqueous cis MeVal11-MeBmt1 state (A1) to the closed conformation featuring cis MeLeu9-MeLeu10 (C1) in facilitating membrane permeation. Additionally, we highlight that the transition from A1 to the all-trans open conformation (O1) is specifically triggered by the presence of CaCl2. We also capture a set of conformers with cis Sar3-MeLeu4, MeLeu9-MeLeu10, denoted as I. Conformationally selected cIMS-MS and IRMPD data of [CycA+Ca]2+ show immediate repopulation of the original population distribution, suggesting that CaCl2 smooths out the energy barriers. Finally, our work presents an improved sampling molecular dynamics approach based on a refined force field that not only consistently and accurately captures established conformers of cyclosporines but also exhibits strong predictive capabilities for novel conformers.

Revealing the Role of Noncovalent Interactions on the Conformation of the Methyl Group in Tricyclic Orthoamide.

Tricyclic orthoamides are valuable molecules with wide-ranging applications, including organic synthesis and molecular recognition. Their structural properties make them intriguing, particularly the eclipsed all-trans conformer, which is typically less stable than the alternated conformation and is a rare phenomenon in organic chemistry. However, it gains stability in crystalline and hydrated settings, challenging the existing theoretical explanations. This study investigates which factors make eclipsed conformers more stable using experimentally reported anhydrous (ATO) and hydrated (HTO) crystal structures. Employing the quantum theory of atoms in molecules, noncovalent interaction index, and pairwise energy decomposition analysis, we delve into the noncovalent interaction environment surrounding the molecule of interest. In ATO, dispersive interactions dominate, whereas in HTO, both dispersive and electrostatic contributions are observed due to the presence of water molecules. Anchored to the lone pairs of the nitrogen atom in the orthoamide tricycle, water molecules prompt the methyl group's eclipsing through intermolecular and intramolecular interactions. This work resolves the long-standing conflict behind why tricyclic orthoamide has an eclipsed conformation by establishing the stabilization factors. These insights have implications for crystal engineering and design, enhancing our understanding of structural behavior in both crystalline and hydrated environments.

Optimizing solvent dipole moment enables PVDF to improve piezoelectric performance

The all-trans conformation (β-phase) possesses a significant impact on the piezoelectric polymer polyvinylidene fluoride (PVDF). Inducing more molecular chain [−CH2−CF2−]n to form all-trans conformation is one of the biggest obstacles for manufacturing high-performance piezoelectric sensing devices. Herein, the continuous vacuum technology is used to modulate the polarity of binary solvents by the proportion of the lower solvent. The regulated solvent forms a high dipole moment, an interaction between the dipole of β-phase and the dipole moment makes the phase reversal in PVDF. Fourier transform infrared spectroscopy, piezoelectric constant test and other characterization results show that when the weakly polar acetone and the strongly polar solvent DMF reach a ratio of 4:6, the pure PVDF film possesses high piezoelectricity (d 33 ∼ −44.8 pC N−1) and strong self-polarization. Additionally, the A4D6 device exhibits high sensitivity (S 1 = 0.182 V/N, 0.5 N ∼ 30 N), driven capability (0.49 mW m−2), and reliability during the electrical tests as a pressure device. This work provides an effective and cost-effective route of optimizing the solvent’s polarity to improve the piezoelectric characteristics of the polymer.

Synthesis, crystal structure and Hirshfeld surface analysis of 1-(12-bromo-dodec-yl)indoline-2,3-dione.

In the title compound, C20H28BrNO2, the indoline portion is almost planar and the 12-bromo-dodecyl chain adopts an all-trans conformation apart from the gauche terminal C-C-C-Br fragment. A micellar-like structure is generated in the crystal by C-H⋯O hydrogen bonds and π-stacking inter-actions between indolinedione head groups and inter-calation of the 12-bromo-dodecyl tails. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H⋯H (58.9%), H⋯O/O⋯H (17.9%) and H⋯Br/Br⋯H (9.5%) contacts. A density functional theory (DFT) optimized structure at the B3LYP/ 6-311 G(d,p) level shows good agreement with the experimentally determined mol-ecular structure in the solid state.

Calcite Surfaces Modified with Carboxylic Acids (C2 to C18): Layer Organization, Wettability, Stability, and Molecular Structural Properties.

A fundamental understanding of the interactions between mineral surfaces and amphiphilic surface modification agents is needed for better control over the production and uses of mineral fillers. Here, we controlled the carboxylic acid layer formation conditions on calcite surfaces with high precision via vapor deposition. The properties of the resulting carboxylic acid layers were analyzed using surface-sensitive techniques, such as atomic force microscopy (AFM), contact angle measurements, angle resolved X-ray photoelectron spectroscopy (XPS), and vibrational sum-frequency spectroscopy. A low wettability was achieved with long hydrocarbon chain carboxylic acids such as stearic acid. The stearic acid layer formed by vapor deposition is initially patchy, but with increasing vapor exposure time, the patches grow and condense into a homogeneous layer with a thickness close to that expected for a monolayer as evaluated by AFM and XPS. The build-up process of the layer occurs more rapidly at higher temperatures due to the higher vapor pressure. The stability of the deposited fatty acid layer in the presence of a water droplet increases with the chain length and packing density in the adsorbed layer. Vibrational sum frequency spectroscopy data demonstrate that the stearic acid monolayers on calcite have their alkyl chains in an all-trans conformation and are anisotropically distributed on the plane of the surface, forming epitaxial monolayers. Vibrational spectra also show that the stearic acid molecules interact with the calcite surface through the carboxylic acid headgroup in both its protonated and deprotonated forms. The results presented provide new molecular insights into the properties of adsorbed carboxylic acid layers on calcite.

Strategies for acquisition of resonance assignment spectra of highly dynamic membrane proteins: a GPCR case study.

In protein nuclear magnetic resonance (NMR), chemical shift assignment provides a wealth of information. However, acquisition of high-quality solid-state NMR spectra depends on protein-specific dynamics. For membrane proteins, bilayer heterogeneity further complicates this observation. Since the efficiency of cross-polarization transfer is strongly entwined with protein dynamics, optimal temperatures for spectral sensitivity and resolution will depend not only on inherent protein dynamics, but temperature-dependent phase properties of the bilayer environment. We acquired 1-, 2-, and 3D homo- and heteronuclear experiments of the chemokine receptor CCR3 in a 7:3 phosphatidylcholine:cholesterol lipid environment. 1D direct polarization, cross polarization (CP), and T2' experiments indicate sample temperatures below - 25°C facilitate higher CP enhancement and longer-lived transverse relaxation times. T1rho experiments indicate intermediate timescales are minimized below a sample temperature of - 20°C. 2D DCP NCA experiments indicated optimal CP efficiency and resolution at a sample temperature of - 30°C, corroborated by linewidth analysis in 3D NCACX at - 30°C compared to - 5°C. This optimal temperature is concluded to be directly related the lipid phase transition, measured to be between - 20 and 15°C based on rINEPT signal of all-trans and trans-gauche lipid acyl conformations. Our results have critical implications in acquisition of SSNMR membrane protein assignment spectra, as we hypothesize that different lipid compositions with different phase transition properties influence protein dynamics and therefore the optimal acquisition temperature.

Intramolecular noncovalent interactions in bis-imidazolium dications with short aliphatic spacers

Stretched all-trans conformations were found preferable in computed structures of bis-imidazolium dications with short aliphatic (С1-С4) and hydroxyl substituted -СН2-СНОН-СН2- spacers. Maxima of molecular electrostatic potential were established near С2Н imidazolium and spacer hydrogens, for α,ω-alkenyl spacers, and close to hydroxyl hydrogen for hydroxypropane spacer. Sufficiently higher rotational barrier around С1-C2 bond in -СН2-СНОН-СН2- spacer compared with polymethylene is supported with intramolecular hydrogen bonds С-Н···О-Н between imidazolium hydrogens and hydroxyl oxygen.

Microstructures and Ferroelectric Properties of Poly(vinylidene fluoride-ter-trifluoroethylene-ter-vinyl fluoride) Terpolymers

The incorporation of comonomers as structural defects has been extensively exploited to modulate the structures and physical properties of poly(vinylidene fluoride) (PVDF)-based ferroelectric polymers. Previous studies have shown that the large-sized comonomers can induce relaxor ferroelectricity in the PVDF-based terpolymers as a result of the stabilization of the helical conformation. Here, we show that, with incorporating a small-sized defect, vinyl fluoride (VF), into the copolymer, the resulting terpolymers preferentially adopt the polar all-trans conformation, as revealed by the structural characterizations and confirmed by density functional theory simulations. Consequently, the terpolymers exhibit robust ferroelectricity with an increased ferroelectric-to-paraelectric transition temperature and a higher coercive field as the VF content increases. This work systematically investigates the compositional dependence of the microstructures, crystalline structures, and ferroelectric and electromechanical properties of the terpolymers and stresses the vital role of comonomer size in tailoring the structures and properties of ferroelectric polymers.

Benzyl-hexa-decyl-dimethyl-ammonium chloride dihydrate.

The title compound, C25H46N+·Cl-·2H2O, crystallizes in the space group P21 with one organic mol-ecule in the asymmetric unit. The compound belongs to a class of benzalkonium chlorides (BACs) with an alkyl chain length of 16 carbon atoms in an all-trans conformation.

Identification of a Functionally Efficient and Thermally Stable Outward Sodium-Pumping Rhodopsin (BeNaR) from a Thermophilic Bacterium.

Rhodopsins are transmembrane proteins with retinal chromophores that are involved in photo-energy conversion and photo-signal transduction in diverse organisms. In this study, we newly identified and characterized a rhodopsin from a thermophilic bacterium, Bellilinea sp. Recombinant Escherichia coli cells expressing the rhodopsin showed light-induced alkalization of the medium only in the presence of sodium ions (Na+), and the alkalization signal was enhanced by addition of a protonophore, indicating an outward Na+ pump function across the cellular membrane. Thus, we named the protein Bellilinea Na+-pumping rhodopsin, BeNaR. Of note, its Na+-pumping activity is significantly greater than that of the known Na+-pumping rhodopsin, KR2. We further characterized its photochemical properties as follows: (i) Visible spectroscopy and HPLC revealed that BeNaR has an absorption maximum at 524 nm with predominantly (>96%) the all-trans retinal conformer. (ii) Time-dependent thermal denaturation experiments revealed that BeNaR showed high thermal stability. (iii) The time-resolved flash-photolysis in the nanosecond to millisecond time domains revealed the presence of four kinetically distinctive photointermediates, K, L, M and O. (iv) Mutational analysis revealed that Asp101, which acts as a counterion, and Asp230 around the retinal were essential for the Na+-pumping activity. From the results, we propose a model for the outward Na+-pumping mechanism of BeNaR. The efficient Na+-pumping activity of BeNaR and its high stability make it a useful model both for ion transporters and optogenetics tools.

Ultrafast structural changes direct the first molecular events of retinal isomerisation and rhodopsin activation.

Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs). A photon is absorbed by the 11-cis retinal chromophore of rhodopsin which isomerises within 200 femtoseconds to the all-trans conformation. In this work, we use ultrafast time-resolved crystallography at room temperature to determine how an isomerised twisted all-trans retinal stores the photon energy required to initiate retinal isomerization. The distorted retinal at 1 ps time-delay of photoactivation has reduced its numerous interactions with the amino acids in its binding pocket. The excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Strikingly, the very early structural motions in the protein side chains of rhodopsin appear in regions involved in later stages of the conserved Class A GPCR activation mechanism. This indicates a conserved energy dissipation pathway and a dual function of the internal hydrogen bond networks of the GPCR linked to its dynamic conformational landscape. Our ultrafast free electron laser measurements shed light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of photo activation of retinal proteins.

High-performance piezoelectric composites via β phase programming

Polymer-ceramic piezoelectric composites, combining high piezoelectricity and mechanical flexibility, have attracted increasing interest in both academia and industry. However, their piezoelectric activity is largely limited by intrinsically low crystallinity and weak spontaneous polarization. Here, we propose a Ti3C2Tx MXene anchoring method to manipulate the intermolecular interactions within the all-trans conformation of a polymer matrix. Employing phase-field simulation and molecular dynamics calculations, we show that OH surface terminations on the Ti3C2Tx nanosheets offer hydrogen bonding with the fluoropolymer matrix, leading to dipole alignment and enhanced net spontaneous polarization of the polymer-ceramic composites. We then translated this interfacial bonding strategy into electrospinning to boost the piezoelectric response of samarium doped Pb (Mg1/3Nb2/3)O3-PbTiO3/polyvinylidene fluoride composite nanofibers by 160% via Ti3C2Tx nanosheets inclusion. With excellent piezoelectric and mechanical attributes, the as-electrospun piezoelectric nanofibers can be easily integrated into the conventional shoe insoles to form a foot sensor network for all-around gait patterns monitoring, walking habits identification and Metatarsalgi prognosis. This work utilizes the interfacial coupling mechanism of intermolecular anchoring as a strategy to develop high-performance piezoelectric composites for wearable electronics.

Crystal structure of 8-hex-yloxy-2-[(Z)-2-(naph-thal-en-2-yl)ethen-yl]quinoline.

In the title mol-ecule, C27H27NO, the naphthalene and quinoline groups are both planar and subtend a dihedral angle of 15.47 (7)°. They are nearly coplanar with the cis-vinyl bridge and the hex-yloxy chain, which adopts an all-trans conformation, resulting in transannular bifurcated intra-molecular C-H⋯N,O contact. The crystal structure features γ-packing of the aromatic moieties, while the parallel packing of alkyl chains resembles that of alkanes.

Polymorphism at hexadecanoic-acid crystals investigated through structural and vibrational studies

Hexadecanoic acid (HA) is a saturated fatty acid with wide industrial application due to its important chemical and physical properties. However, understanding of its polymorphic characteristics under a specific growth condition is still an open question. This paper shows HA crystals grown by the slow evaporation method with five different solvents. The polymorphism was evaluated by X-ray diffraction, Raman and Fourier-transform infrared (FT-IR) spectroscopy. Most of the crystals presented two main polymorphic phases, and the C polymorphic form common among samples appeared as a progressive increase with increasing solvent polarity. Nevertheless, solvents with slower evaporation allowed to obtain the Bm form as a minor phase. Furthermore, polar solvents with rapid evaporation allowed the growth of the Em form as a secondary phase. Vibrational analysis on the Raman- and IR-active bands indicated that almost all inter-molecular modes are more likely to gauche conformation than all-trans conformation. This behavior is due to changes in the hydrogen bonds (O−H.O) and, mainly, in the C-C bonds around the carboxylic group (COOH) that form the dimers between the pairs of molecules within the crystalline lattice.

Influence of Aliphatic Chain Length on Structural, Thermal and Electrochemical Properties of n-alkylene Benzyl Alcohols: A Study of the Odd-Even Effect.

The century-old, well-known odd–even effect phenomenon is still a very attractive and intriguing topic in supramolecular and nano-scale organic chemistry. As a part of our continuous efforts in the study of supramolecular chemistry, we have prepared three novel aromatic alcohols (1,2-bis[2-(hydroxymethyl)phenoxy]butylene (Do4OH), 1,2-bis[2-(hydroxymethyl)phenoxy]pentylene (Do5OH) and 1,2-bis[2-(hydroxymethyl)phenoxy]hexylene (Do6OH)) and determined their crystal and molecular structures by single-crystal X-ray diffraction. In all compounds, two benzyl alcohol groups are linked by an aliphatic chain of different lengths (CH2)n; n = 4, 5 and 6. The major differences in the molecular structures were found in the overall planarity of the molecules and the conformation of the aliphatic chain. Molecules with an even number of CH2 groups tend to be planar with an all-trans conformation of the aliphatic chain, while the odd-numbered molecule is non-planar, with partial gauche conformation. A direct consequence of these structural differences is visible in the melting points—odd-numbered compounds of a particular series display systematically lower melting points. Crystal and molecular structures were additionally studied by the theoretical calculations and the melting points were correlated with packing density and the number of CH2 groups. The results have shown that the generally accepted rule, higher density = higher stability = higher melting point, could not be applied to these compounds. It was found that the denser packaging causes an increase in the percentage of repulsive H‧‧‧H interactions, thereby reducing the stability of the crystal, and consequently, the melting points. Another interesting consequence of different molecular structures is their electrochemical and antioxidative properties—a non-planar structure displays the highest oxidation peak of hydroxyl groups and moderate antioxidant activity.

Superhalogen Anions Supported by the Systems Comprising Alternately Aligned Boron and Nitrogen Central Atoms.

Using DFT/(B3LYP/wB97XD/B2PLYPD) and OVGF electronic structure methods with flexible atomic orbital basis sets, we examined the series of polynuclear superhalogen anions matching the (BF3(BN) n F4n+1)– formula (for n = 1-10,13,18-20) containing alternately aligned boron and nitrogen central atoms decorated with fluorine ligands. It was found that the equilibrium structures of these anions correspond to fully extended chains (with each B and N central atom surrounded by four substituents arranged in a tetrahedral manner) and thus mimic the globally stable fully extended (all-trans) conformations of higher n-alkanes. The vertical electron detachment energies of the (BF3(BN) n F4n+1)– anions were found to exceed 8 eV in all cases and gradually increase with the increasing number of n. The approximate limiting value of vertical electron binding energy that could be achieved for such polynuclear superhalogen anions was estimated as equal to ca. 10.7 eV.

Dependency of the twist-bend nematic phase formation on the molecular shape of liquid crystal dimers: A view through the lens of DFT

In view of the importance of molecular structural features, particularly the molecular curvature, that form the basis for the appearance and stabilization of the twist-bend nematic (Ntb) phase, the present work reports a computational study on a set of cyanobiphenyl dimers. In these dimers, the chemical nature of the linkage between the spacer and mesogenic units has been systematically varied by incorporating either methylene, ether, or thioether groups. Through computational modeling, we calculated the bend angle between the two mesogenic arms from all-trans conformations as well as Boltzmann-weighted average bend angle from conformational ensembles for each dimer. It was observed that the incidence of the Ntb phase is not only sensitive to the degree of molecular bend angle but also the conformational distribution. The present analysis recognized that the Ntb phase is only seen in liquid crystal dimers that have a sufficiently bent molecular structure. In addition, we have found a strong dependency of transitional properties upon these molecular factors. The changes in the phase transition temperatures appear to be a direct consequence of discrete changes in the molecular bend angle, as this is the major difference when comparing these dimers.

Spectroscopic signatures of bilayer ordering in native biological membranes

Membrane proteins and polycyclic lipids like cholesterol and hopanoids coordinate phospholipid bilayer ordering. This phenomenon manifests as partitioning of the liquid crystalline phase into liquid-ordered (Lo) and liquid-disordered (Ld) regions. In Eukaryotes, microdomains are rich in cholesterol and sphingolipids and serve as signal transduction scaffolds. In Prokaryotes, Lo microdomains increase pathogenicity and antimicrobial resistance. Previously, we identified spectroscopically distinct chemical shift signatures for all-trans (AT) and trans-gauche (TG) acyl chain conformations, cyclopropyl ring lipids (CPR), and hopanoids in prokaryotic lipid extracts and used Polarization Transfer (PT) SSNMR to investigate bilayer ordering. To investigate how these findings relate to native bilayer organization, we interrogate whole cell and whole membrane extract samples of Burkholderia thailendensis to investigate bilayer ordering in situ. In 13C-13C 2D SSNMR spectra, we assigned chemical shifts for lipid species in both samples, showing conservation of lipids of interest in our native membrane sample. A one-dimensional temperature series of PT SSNMR and transverse relaxation measurements of AT versus TG acyl conformations in the membrane sample confirm bilayer ordering and a broadened phase transition centered at a lower-than-expected temperature. Bulk protein backbone Cα dynamics and correlations consistent with lipid-protein contacts within are further indicative of microdomain formation and lipid ordering. In aggregate, these findings provide evidence for microdomain formation in vivo and provide insight into phase separation and transition mechanics in biological membranes.

Exploration of the Nucleation-Growth Effect of Cetyltrimethylammonium Bromide for High β-Poly(Vinylidene Fluoride) Crystallization

Poly(vinylidene fluoride) (PVDF, β-phase) exhibits excellent electrical properties because of its all-trans conformation in the crystalline phase, which has attracted much attention in electronic device applications. This paper describes our studies of the cetyltrimethylammonium bromide (CTAB)-induced PVDF crystallization in PVDF thin films via solution crystallization and melt crystallization by compression molding. In the solution crystallization process the relative crystal content of the polar crystals phase of PVDF reached 90% due to the solvent effect and low crystallization temperature. During the melt crystallization process the polar crystal nucleation effect of CTAB (powders) was pronounced. The strong "ion-dipole" interaction between the positive charges on the surface of CTAB and the -CF2 of PVDF promoted the formation of polar crystals. The incorporation of 1 wt% CTAB in PVDF led to the nucleation of polar crystallites up to 97.6%. Additionally, the tensile strength and elongation at break reached 39.8 MPa and 172.5%. The crystallinity of the PVDF increased with an increase in the content of CTAB. The electrostatic interaction between CTAB and the PVDF molecular chains induced and stabilized the all-trans conformation of the PVDF crystals, resulting in PVDF films with high polar phase content, which are expected to be applicable to industrially produced piezoelectric films.