Intramolecular Dynamics Research Articles

Studying the Intermolecular Interactions, Structural Dynamics, and Non-Equilibrium Kinetics of Cilnidipine Infiltrated into Alumina and Silica Pores.

In the present study, the behavior of the calcium channel blocker cilnidipine (CLN) infiltrated into silica (SiO2) and anodic aluminum oxide (AAO) porous membranes characterized by a similar pore size (d = 8 nm and d = 10 nm, respectively) as well as the bulk sample has been investigated using differential scanning calorimetry, broadband dielectric spectroscopy (BDS), and Fourier-transform infrared spectroscopy (FTIR) techniques. The obtained data suggested the existence of two sets of CLN molecules in both confined systems (core and interfacial). They also revealed the lack of substantial differences in inter- and intramolecular dynamics of nanospatially restricted samples independently of the applied porous membranes. Moreover, the annealing experiments (isothermal time-dependent measurements) performed on the confined CLN clearly indicated that the whole equilibration process under confinement is governed by structural relaxation. It was also found that the βanneal parameters obtained from BDS and FTIR data upon equilibration of both confined samples are comparable (within 10%) to each other, while the equilibration constants are significantly different. This finding strongly emphasizes that there is a close connection between the inter- and intramolecular dynamics under nanospatial restriction.

Recent Progress in Biosensors for Diagnosis of Cancer Cells, Tissues and Tumors Biomarkers

Raman spectroscopy is an important method for identifying molecules, which is widely used in determining the chemical and structural characteristics of various substances. Many materials have a special Raman spectrum, so that this phenomenon has turned the Raman device into an efficient tool for studying the structural and chemical properties of molecules. Since it is possible to obtain detailed information about the chemical and structural characteristics of biological compounds from Raman spectroscopy, the use of this method is rapidly expanding in the field of life sciences, especially in biological and medical studies. There is no need for special, time-consuming and expensive preparations in the study of materials with the help of a Raman device. In the protein Raman spectrum, distinct bands arise from the vibrational states of the peptide backbone and amino acid side chains. Therefore, based on the position and intensity of the protein’s Raman spectrum, it is possible to obtain valuable information about its second, third, and fourth structures. Also, the Raman spectrum of the protein contains information about the orientation and surrounding environment of the amino acid side chains. The correct formation of the disulfide bond in the protein structure can also be studied with the help of the Raman device. In general, the Raman spectrum of proteins contains multiple discrete bands that represent the vibrational states of the molecule and is used as a selective fingerprint to accurately determine the three–dimensional structure of proteins, intramolecular dynamics, and intermolecular interactions (Graphical Abstract).

A Crystalline Dimeric Steroidal Diboronate with Electronically Impeded Rotation

The dimeric steroid SMR-3, featuring a 1,4-phenyldiboronic ester flanked by two pregnan-triol frameworks, was synthesized to explore the intramolecular dynamics of its central component. The structural data from single-crystal X-ray diffraction studies and the Hirshfeld analyses indicate small steric effects around the aromatic ring that should favor the intended motion. However, solid-state NMR data obtained through VT 13C{1H} CPMAS and 2H spin-echo experiments, using the deuterated analogue SMR-3D4, revealed that this component is rigid even at temperatures where other reported steroidal molecular rotors experience fast rotation (85 °C). A combination of classical molecular dynamics, molecular mechanics, and correlated ab initio calculations allowed us to distinguish the steric and electronic factors that restrict the potential motion in this compound. The experimental and computational data reveal that electronic components dominate the behavior and are responsible for the high rotational barrier in the SMR-3 crystal.

Leading–Edge Portable Biosensors and Biomarkers Development for Raman Biospectroscopy and Imaging in Cancer Diagnosis

Raman spectroscopy is an important method for identifying molecules, which is widely used in determining the chemical and structural characteristics of various substances. Many materials have a special Raman spectrum, so that this phenomenon has turned the Raman device into an efficient tool for studying the structural and chemical properties of molecules. Since it is possible to obtain detailed information about the chemical and structural characteristics of biological compounds from Raman spectroscopy, the use of this method is rapidly expanding in the field of life sciences, especially in biological and medical studies. There is no need for special, time–consuming and expensive preparations in the study of materials with the help of a Raman device. In the protein Raman spectrum, distinct bands arise from the vibrational states of the peptide backbone and amino acid side chains. Therefore, based on the position and intensity of the protein's Raman spectrum, it is possible to obtain valuable information about its second, third, and fourth structures. Also, the Raman spectrum of the protein contains information about the orientation and surrounding environment of the amino acid side chains. The correct formation of the disulfide bond in the protein structure can also be studied with the help of the Raman device. In general, the Raman spectrum of proteins contains multiple discrete bands that represent the vibrational states of the molecule and is used as a selective fingerprint to accurately determine the three–dimensional structure of proteins, intramolecular dynamics, and intermolecular interactions.

Visualizing Intramolecular Dynamics of Membrane Proteins

Membrane proteins play important roles in biological functions, with accompanying allosteric structure changes. Understanding intramolecular dynamics helps elucidate catalytic mechanisms and develop new drugs. In contrast to the various technologies for structural analysis, methods for analyzing intramolecular dynamics are limited. Single-molecule measurements using optical microscopy have been widely used for kinetic analysis. Recently, improvements in detectors and image analysis technology have made it possible to use single-molecule determination methods using X-rays and electron beams, such as diffracted X-ray tracking (DXT), X-ray free electron laser (XFEL) imaging, and cryo-electron microscopy (cryo-EM). High-speed atomic force microscopy (HS-AFM) is a scanning probe microscope that can capture the structural dynamics of biomolecules in real time at the single-molecule level. Time-resolved techniques also facilitate an understanding of real-time intramolecular processes during chemical reactions. In this review, recent advances in membrane protein dynamics visualization techniques were presented.

A study of O[sbnd]H···O hydrogen bonds along various isolines in 2-ethyl-1-hexanol. Temperature or pressure - which parameter controls their behavior?

The nature of H-bonding interactions is still far from being understood despite intense experimental and theoretical studies on this subject carried out by the leading research centers. In this paper, by a combination of unique high-pressure infrared, dielectric and volumetric data, the intramolecular dynamics of hydroxyl moieties (which provides direct information about H-bonds) was studied along various isolines, i.e., isotherms, isobars, isochrones, and isochores, in a simple monohydroxy alcohol (2-ethyl-1-hexanol). This allowed us to discover that the temperature controls the intermolecular hydrogen bonds, which then affect the intramolecular dynamics of OH units. Although the role of density fluctuations gets stronger as temperature rises. We also demonstrated a clear connection between the intra- and intermolecular dynamics of the associating liquid at high pressure. The data reported herein open a new perspective to explore this important aspect of the glass transition phenomenon and understand H-bonding interactions at varying thermodynamic conditions.

Dramatic Impact of Auxiliary Ligands on the Dynamic Magnetic Relaxation in Tetranuclear DyIII2ZnII2 Single Molecule Magnets

Comprehensive SummaryBetter understanding the determining factors of dynamic magnetic relaxation in polynuclear lanthanide based single‐molecule magnets (SMMs) remains a challenge due to the complexity of such architectures involving interactions between the magnetic centers. To address this issue, two structurally related heterometal DyIII2ZnII2 SMMs, [Zn2Dy2(L)4(Ac)2(DMF)(CH3OH)]·CH3OH·2H2O (1) and [Zn2Dy2(L)4(Ac)2(DMF)2]·4CH3CN (2) (H2L = (E)‐2‐((2‐hydroxy‐3‐methoxybenzylidene)amino)‐4‐methyphenol, DMF = N,N‐dimethylformamide), are introduced and investigated. Through modifying the auxiliary ligands on one DyIII site while retaining that on the other DyIII, the intramolecular magnetic interactions and relaxation dynamics in these two heterometallic‐DyIII2ZnII2 SMMs can be tuned, demonstrating a dramatic change in the magnet relaxation behavior with energy barrier changing from a negligible value for 1 to 305 K for 2. Ab initio calculations reveal that changing the coordination geometries on the DyIII sites can significantly affect the magnetic interactions as well as single‐ion anisotropy.

Ultrafast intramolecular charge transfer dynamics and nonlinear optical properties of phenothiazine-based push–pull zinc porphyrin

Comprehensive investigations of the ultrafast photophysical properties and charge injection dynamics (adsorbed on mesoporous TiO2) of phenothiazine-functionalized push–pull Zinc porphyrin (LG6) utilizing a benzothiadiazole (BTD) as an acceptor unit is presented herewith. This includes density functional theory (DFT) calculations, fluorescence measurements, time-dependent fluorescence measurements, and femtosecond transient absorption (fs-TA) spectroscopy measurements. The charge injection dynamics of LG6 were compared with another porphyrin, LG5, with a similar molecular structure but thiophene as the acceptor unit instead of BTD. The multicomponent electron injection analysis from different excited electronic energy levels reveals ultrafast electron injection times of 434 fs and 336 fs for LG6 and LG5, respectively, revealing the impact of acceptor units on charge injection times. Further, femtosecond nonlinear optical (NLO) properties were characterized using the femtosecond Z-scan measurements with 70 fs, 800 nm pulses. The analysis of Z-scan open aperture data has been performed by solving three-level rate equations incorporating excited-state lifetimes calculated from the target/global analysis of fs-TA data set. The estimated NLO parameters and ultrafast NLO response times of LG6 indicated the strong potential for optical limiting and optical signal processing applications. The second hyperpolarizability was estimated to be γ=2.5×10-31esu, which was found to be in close agreement with the theoretically calculated value of 0.4×10-31e.s.u.

Intramolecular vibrational redistribution in formic acid and its deuterated forms.

The intramolecular vibrational relaxation dynamics of formic acid and its deuterated isotopologues is simulated on the full-dimensional potential energy surface of Richter and Carbonnière [J. Chem. Phys. 148, 064303 (2018)] using the Heidelberg MCTDH package. We focus on couplings with the torsion vibrational modes close to the trans-cis isomerization coordinate from the dynamics of artificially excited vibrational mode overtones. The bright C-O stretch vibrational mode is coupled to the out-of-the plane torsion mode in HCOOH, where this coupling could be exploited for laser-induced trans-to-cis isomerization. Strong isotopic effects are observed: deuteration of the hydroxyl group, i.e., in HCOOD and DCOOD, destroys the C-O stretch to torsion mode coupling whereas in DCOOH, little to no effect is observed.

Diffracted X-ray Tracking Method for Measuring Intramolecular Dynamics of Membrane Proteins.

Membrane proteins change their conformations in response to chemical and physical stimuli and transmit extracellular signals inside cells. Several approaches have been developed for solving the structures of proteins. However, few techniques can monitor real-time protein dynamics. The diffracted X-ray tracking method (DXT) is an X-ray-based single-molecule technique that monitors the internal motion of biomolecules in an aqueous solution. DXT analyzes trajectories of Laue spots generated from the attached gold nanocrystals with a two-dimensional axis by tilting (θ) and twisting (χ). Furthermore, high-intensity X-rays from synchrotron radiation facilities enable measurements with microsecond-timescale and picometer-spatial-scale intramolecular information. The technique has been applied to various membrane proteins due to its superior spatiotemporal resolution. In this review, we introduce basic principles of DXT, reviewing its recent and extended applications to membrane proteins and living cells, respectively.

Solvated Nuclear-Electronic Orbital Structure and Dynamics.

Nonadiabatic dynamical processes such as proton-coupled electron transfer and excited state intramolecular proton transfer have been the subject of much research. One of the promising theoretical methods to describe these processes is the nuclear-electronic orbital (NEO) approach. This approach inherently accounts for nuclear quantum effects within quantum chemistry calculations, and it has recently been extended to directly simulate nonadiabatic processes with the development of real-time NEO methods. These processes can also be significantly dependent on the surrounding chemical environment, however, and capturing the effects of the environment is often necessary for analyzing experimentally relevant systems. This work couples the NEO density functional theory and real-time time-dependent density functional theory approaches with solvation through the polarizable continuum model. The effects of this coupling are investigated for ground state properties, solvent-dependent vibrational frequencies, and direct excited state intramolecular proton transfer dynamics.

Glassy dynamics in polyalcohols: intermolecular simplicity vs. intramolecular complexity.

Using depolarized light scattering, we have recently shown that structural relaxation in a broad range of supercooled liquids follows, to good approximation, a generic line shape with high-frequency power law ω-1/2. We now continue this study by investigating a systematic series of polyalcohols (PAs), frequently used as model-systems in glass-science, i.a., because the width of their respective dielectric loss spectra varies strongly along the series. Our results reveal that the microscopic origin of the observed relaxation behavior varies significantly between different PAs: while short-chained PAs like glycerol rotate as more or less rigid entities and their light scattering spectra follow the generic shape, long-chained PAs like sorbitol display pronounced intramolecular dynamic contributions on the time scale of structural relaxation, leading to systematic deviations from the generic shape. Based on these findings we discuss an important limitation for observing the generic shape in a supercooled liquid: the dynamics that is probed needs to reflect the intermolecular dynamic heterogeneity, and must not be superimposed by effects of intramolecular dynamic heterogeneity.

Quantum dynamics of intramolecular CCOH torsional motions in 1-Naphthol followed through the OH stretching chromophore

Intramolecular vibrational dynamics of CCOH torsions and OH stretching vibrations in 1-naphthol were followed by Fourier transform infrared (FTIR) spectroscopy and quantum-theoretical computations. The possibility of unintentional trans → cis transformation induced by broad- and narrowband incident IR radiation during the standard IR experiment was considered in detail. Spontaneous transitions from cis to trans rotamer by both classical rotation over the potential barrier as well as by quantum tunneling were analyzed by combining experimental data and theoretical calculations. Torsional correlation times for the cis → trans transitions were calculated by purely classical and quantum mechanical approaches. Both adiabatic and diabatic torsional potentials were considered in this context. At the same time, Anharmonic vibrational frequencies of the OH stretching chromophore were calculated within a one-dimensional approximation for both cis and trans conformers of 1 -naphthol. This was done by carrying out a series of pointwise energy calculations at series of intramolecular geometries corresponding to excitation of the OH stretching local mode, subsequently fitting the data to a fifth-order polynomial function, transforming the bond stretching coordinates to Simons-Parr-Finlan coordinates and finally numerically solving the vibrational Schrödinger equation by variational technique. Excellent agreement between theoretical calculations (carried out at MP2/6-311++G(3df,3pd) and B3LYP/6-311++G(3df,3pd) levels) and experimental data were obtained for the differences in OH stretching frequencies in trans and cis conformers (Δv(trans→cis)ex.= +13cm1, Δv(trans→cis) B3LYP. = +12.6 cm1). Frequency blue shift-induced upon trans → cis conformational change occurs as a consequence of intramolecular vibrational confinement. The OH stretching chromophore is a very sensitive probe for both intra- and intermolecular dynamics of the title system. It is therefore a rather significant indicator of the molecular environment in condensed phase systems.

Structural Features of Cytochrome b5-Cytochrome b5 Reductase Complex Formation and Implications for the Intramolecular Dynamics of Cytochrome b5 Reductase.

Membrane cytochrome b5 reductase is a pleiotropic oxidoreductase that uses primarily soluble reduced nicotinamide adenine dinucleotide (NADH) as an electron donor to reduce multiple biological acceptors localized in cellular membranes. Some of the biological acceptors of the reductase and coupled redox proteins might eventually transfer electrons to oxygen to form reactive oxygen species. Additionally, an inefficient electron transfer to redox acceptors can lead to electron uncoupling and superoxide anion formation by the reductase. Many efforts have been made to characterize the involved catalytic domains in the electron transfer from the reduced flavoprotein to its electron acceptors, such as cytochrome b5, through a detailed description of the flavin and NADH-binding sites. This information might help to understand better the processes and modifications involved in reactive oxygen formation by the cytochrome b5 reductase. Nevertheless, more than half a century since this enzyme was first purified, the one-electron transfer process toward potential electron acceptors of the reductase is still only partially understood. New advances in computational analysis of protein structures allow predicting the intramolecular protein dynamics, identifying potential functional sites, or evaluating the effects of microenvironment changes in protein structure and dynamics. We applied this approach to characterize further the roles of amino acid domains within cytochrome b5 reductase structure, part of the catalytic domain, and several sensors and structural domains involved in the interactions with cytochrome b5 and other electron acceptors. The computational analysis results allowed us to rationalize some of the available spectroscopic data regarding ligand-induced conformational changes leading to an increase in the flavin adenine dinucleotide (FAD) solvent-exposed surface, which has been previously correlated with the formation of complexes with electron acceptors.

Organic Host Encapsulation Effects on Nitrosobenzene Monomer-Dimer Distribution and C-NO Bond Rotation in an Aqueous Solution.

The intermolecular (monomer-dimer equilibrium) and intramolecular (C-NO and C-NMe2 rotations) dynamics of 4-nitrosocumene (1a) and 4-(N,N-dimethylamino)nitrosobenzene (1b), respectively, were found to be controlled by the medium (water) and the host environment (organic capsules and cavitands). The ability of water to shift the equilibrium toward the dimer appears to result from dipolar stabilization of the polar dimer structure and has a resemblance to water's known ability to favor organic cycloaddition reactions. In an aqueous medium, a range of organic hosts selectively include only the nitrosocumene monomer 1a. Encapsulation in the octa acid duplex (OA2) selects two 1a monomers rather than a dimer structure. Octa acid encapsulation also results in more restricted intramolecular C-N rotations of the guest 1b.

Intramolecular charge transfer of coumarin dyes confined in methanol-in-oil reverse micelles

The reverse micelles (RMs) of bis(2-ethylhexyl)sulfosuccinate sodium salt (AOT) are considered as a model system for the molecular dynamics investigation of small chromophores, where the micelle-size-dependent dynamics are interpreted as the unique solvent properties in the core of RMs. The sizes of RMs are practically proportional to the molar ratio between polar solvent and surfactant. However, the formation of RMs with nonaqueous polar solvents methanol or acetonitrile is not clearly understood yet. In this work, we have shown that the formation of RMs with methanol core depends strongly on the concentration of surfactant AOT by the experimental evidence of the absorption, emission, and Raman spectroscopic measurements. In addition, the intramolecular charge transfer dynamics of coumarin 481 (C481) and coumarin 153 in methanol RMs were investigated by steady-state and time-resolved electronic spectroscopy, where the differences of the excited-state dynamics in the RMs are understood as the effect of the molecular rotation of diethylamino group of C481.

Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases.

Safinamide mesylate (SM), the pure active pharmaceutical ingredient (API) recently used in Parkinson disease treatment, recrystallized employing water–ethanol mixture of solvents (vol/vol 1:9) gives a different crystallographic form compared to SM in Xadago tablets. Pure SM crystallizes as a hemihydrate in the monoclinic system with the P21 space group. Its crystal and molecular structure were determined by means of cryo X-ray crystallography at 100 K. SM in the Xadago tablet exists in anhydrous form in the orthorhombic crystallographic system with the P212121 space group. The water migration and thermal processes in the crystal lattice were monitored by solid-state NMR spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. SM in Xadago in the high-humidity environment undergoes phase transformation to the P21 form which can be easily reversed just by heating up to 80 °C. For the commercial form of the API, there is also a reversible thermal transformation observed between Z′ = 1 ↔ Z′ = 3 crystallographic forms in the 0–20 °C temperature range. Analysis of molecular motion in the crystal lattice proves that the observed conformational polymorphism is forced by intramolecular dynamics. All above-mentioned processes were analyzed and described employing the NMR crystallography approach with the support of advanced theoretical calculations.

Lanthanide complexes with polyaminopolycarboxylates as prospective NMR/MRI diagnostic probes: peculiarities of molecular structure, dynamics and paramagnetic properties.

The paramagnetic lanthanide complexes with polyaminopolycarboxylate (PAPC) ligands attract considerable attention from the standpoint of potential applications thereof as relaxation agents used in medical magnetic resonance imaging (MRI) and in luminescent materials, as well as owing to promising use thereof as paramagnetic labels for studying the properties of biopolymers since they exhibit thermodynamic stability, good solubility in aqueous media and moderate toxicity. For the last decades, the NMR methods have been used to determine the physical and chemical properties of paramagnetic Ln compounds. The studies concerning paramagnetic NMR lanthanide-induced shifts (LISs) in dissolved Ln complexes, as well as the analysis of band shape as a function of temperature make it possible to obtain valuable information on the structure, intra- and intermolecular dynamics and paramagnetic properties thereof. This review is devoted solely to the following features: firstly, the processes of intramolecular dynamics of lanthanide complexes with polyamino-polycarboxylate ligands such as DOTA, EDTA and DTPA and their derivatives studied by NMR; secondly, the LISs of lanthanide complexes with EDTA, DOTA, DTPA and some of their derivatives depending on temperature and pH. Moreover, in this review, for the first time, the dependence of the activation energy of molecular dynamics in complexes with polydentate ligands on the atomic number of the lanthanide cation is analyzed and a monotonic change in energy is detected, which is due to the effect of lanthanide contraction. It should be noted that this phenomenon is quite general and may also appear in the future in many other series of lanthanide complexes with both other multidentate ligands and with bidentate and monodentate ligands. In the future, it is possible to predict the dependence of the properties of certain lanthanide complexes on the ionic radius of the lanthanide cation based on the approaches presented in the review. In this review, we have also presented the dynamic NMR as the main research method widely used to analyze the processes of molecular dynamics, and the structural studies based on the NMR relaxation spectroscopy and LIS analysis.

Intramolecular Relaxation Dynamics Mediated by Solvent-Solute Interactions of Substituted Fluorene Derivatives. Solute Structural Dependence.

Several fluorene derivatives exhibit excited-state reactivity and relaxation dynamics that remain to be understood fully. We report here the spectral relaxation dynamics of two fluorene derivatives to evaluate the role of structural modification in the intramolecular relaxation dynamics and intermolecular interactions that characterize this family of chromophores. We have examined the time-resolved spectral relaxation dynamics of two compounds, NCy-FR0 and MK-FR0, in protic and aprotic solvents using steady-state and time-resolved emission spectroscopy and quantum chemical computations. Both compounds exhibit spectral relaxation characteristics similar to those seen in FR0, indicating that hydrogen bonding interactions between the chromophore and solvent protons play a significant role in determining the relaxation pathways available to three excited electronic states.

Structure dynamics of HIV-1 Env trimers on native virions engaged with living T cells

The HIV-1 envelope glycoprotein (Env) mediates viral entry into the host cell. Although the highly dynamic nature of Env intramolecular conformations has been shown with single molecule spectroscopy in vitro, the bona fide Env intra- and intermolecular mechanics when engaged with live T cells remains unknown. We used two photon fast fluorescence lifetime imaging detection of single-molecule Förster Resonance Energy Transfer occurring between fluorescent labels on HIV-1 Env on native virions. Our observations reveal Env dynamics at two levels: transitions between different intramolecular conformations and intermolecular interactions between Env within the viral membrane. Furthermore, we show that three broad neutralizing anti-Env antibodies directed to different epitopes restrict Env intramolecular dynamics and interactions between adjacent Env molecules when engaged with living T cells. Importantly, our results show that Env-Env interactions depend on efficient virus maturation, and that is disrupted upon binding of Env to CD4 or by neutralizing antibodies. Thus, this study illuminates how different intramolecular conformations and distribution of Env molecules mediate HIV-1 Env–T cell interactions in real time and therefore might control immune evasion.