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We carried out a first-principles quantum-mechanical study of a set of full-turn A-form DNA oligonucleotides using density functional approximations. The structural features of the fully relaxed model DNA molecules and more importantly, the energetic and structural changes of these molecules under stretching conditions are examined in detail. Special attention is paid to the dependence of the structural properties on the stacking sequences of the constituent DNA base pairs. It appears that DNA oligonucleotides are extremely flexible, and structural properties such as the diameter and the widths of the minor and major grooves change regularly as a function of the stretching rate (stretching length in percentage). Additionally, we found that the length of the hydrogen bonds in the DNA base pairs varies with the DNA stacking sequence. This work indicates that rich information and insights can be gained from first principles studies of model DNA molecules of only O (1 0 2 − 1 0 3 ) atoms. [ABSTRACT FROM AUTHOR] more...

Hydrogen bonds are the key interaction that establishes the liquid and solvent properties of water. Nevertheless, it is possible to construct an accurate molecular model of water which does not include hydrogens or any orientational interactions. Using this model, we calculate the structural and thermodynamic properties for the hydration of methane and ethane. The addition of the hydrophobic solute leads to changes in structure, as can be seen in slightly enhanced tetrahedral geometries and slightly reduced Voronoi volumes of water near the solute. The entropy of hydration from the model is about half the experimental value, suggesting that what is left out of the model—the orientational or hydrogen response—contributes to about half the entropy. For the hydrophobic association of two methane molecules in water, the hydrogen degrees of freedom do not seem to play an important role and the entropy of association is similar to all-atom models. [ABSTRACT FROM AUTHOR] more...

The remarkable and sometimes anomalous properties of water can be traced back at the molecular level to the tetrahedral coordination of molecules due to the ability of a water molecule to form four hydrogen bonds to its neighbors; this feature allows for the formation of a network that greatly influences the thermodynamic behavior. Computer simulations are becoming increasingly important for our understanding of water. Molecular models of water, such as SPC/E, are needed for this purpose, and they have proved to capture many important features of real water. Modifications of the SPC/E model have been proposed, some changing the H-O-H angle (bent models) and others increasing the importance of dispersion interactions (hybrid models), to study the structural features that set water apart from other polar fluids and from simple fluids such as argon. Here, we focus on the properties at liquid-vapor equilibrium and study the coexistence curve, the interfacial tension, and the vapor pressure in a corresponding-states approach. In particular, we calculate Guggenheim's ratio for the reduced apparent enthalpy of vaporization and Guldberg's ratio for the reduced normal boiling point. This analysis offers additional insight from a more macroscopic, thermodynamic perspective and augments that which has already been learned at the molecular level from simulations. In the hybrid models, the relative importance of dispersion interactions is increased, which turns the modified water into a Lennard-Jones-like fluid. Consequently, in a corresponding-states framework, the typical behavior of simple fluids, such as argon, is seen to be approached asymptotically. For the bent models, decreasing the bond angle turns the model essentially into a polar diatomic fluid in which the particles form linear molecular arrangements; as a consequence, characteristic features of the corresponding-states behavior of hydrogen halides emerge. [ABSTRACT FROM AUTHOR] more...

Infrared (IR) spectroscopy of the water O-H stretch has been widely used to probe both the local hydrogen-bonding structure and dynamics of aqueous systems. Although of significant interest, the IR spectroscopy of excess protons in water remains difficult to assign as a result of extensive and strong intermolecular interactions in hydrated proton complexes. As an alternate approach, we develop a mixed quantum-classical model for the vibrational spectroscopy of the excess proton in isotopically dilute water that draws on frozen proton-water clusters taken from reactive molecular dynamics trajectories of the latest generation multi-state empirical valence bond proton model (MS-EVB 3.2). A semi-empirical single oscillator spectroscopic map for the instantaneous transition frequency and transition dipole moment is constructed using potential energy surfaces for the O-H stretch coordinate of the excess proton using electronic structure calculations. Calculated spectra are compared with experimental spectra of dilute H+ in D2O obtained from double-difference FTIR to demonstrate the validity of the map. The model is also used to decompose IR spectra into contributions from different aqueous proton configurations. We find that the O-H transition frequency continuously decreases as the oxygen-oxygen length for a special pair proton decreases, shifting from Eigen- to Zundel-like configurations. The same shift is accompanied by a shift of the flanking water stretches of the Zundel complex to higher frequency than the hydronium O-H vibrations. [ABSTRACT FROM AUTHOR] more...

DNA base pairs are known to open more easily at the helix terminal, a process usually called end fraying, the details of which are still poorly understood. Here, we present a mesoscopic model calculation based on available experimental data where we consider separately the terminal base pairs of a DNA duplex. Our results show an important reduction of hydrogen bond strength for terminal cytosine-guanine (CG) base pairs which is uniform over the whole range of salt concentrations, while for AT base pairs, we obtain a nearly 1/3 reduction but only at low salt concentrations. At higher salt concentrations, terminal adenine-thymine (AT) pair has almost the same hydrogen bond strength than interior bases. The calculated terminal stacking interaction parameters display some peculiarly contrasting behavior. While there is mostly no perceptible difference to internal stacking, for some cases, we observe an unusually strong dependence with salt concentration which does not appear follow any pattern or trend. [ABSTRACT FROM AUTHOR] more...

The functionality of biochar surfaces depends on the nature of the feedstock, pyrolysis temperature, and residence time. In this study, molecular modeling was used to determine the types of functionalization that could enhance adsorption and to pre-screen the target adsorbate for the sake of minimizing experimental time. The impact of a single functional group and interaction between them (including nitrile, methyl, ether, furan, carboxyl, hydroxyl, amine, and amide) on the adsorption of target adsorbate onto biochar was investigated. Among biochars inherent functional groups simulated, the lowest energy of adsorption (highest adsorption) occurred with carboxyl and hydroxyl for CO 2 adsorption due to hydrogen bonding. The simulations showed adding amine/amide functional groups to the biochar surface enhanced CO 2 adsorption, because of stronger bonding. The simulation results were compared against experimental results and the thermodynamic properties were satisfactorily matched. The overall heat of adsorption of H 2 S was lower than CO 2 , but the average Gibbs free energy was approximately the same, indicating CO 2 could replace H 2 S in initial screening adsorption experiments for this type of biochar, reducing costs, risk and toxicity concerns of using H 2 S. This is an example of potentially how the models can be used to better design experiments. Image 1 [ABSTRACT FROM AUTHOR] more...

The well-resolved terahertz (THz) absorption spectrum of barbituric acid has been investigated using terahertz time-domain spectroscopy. Four distinct THz spectral features and two shoulder peaks were observed in the range of 10–124 cm–1. A complete analysis was performed with density functional theory, which provided an excellent agreement between solid-state simulation and experiment. The solid-state analysis indicates that the six experimental spectral features observed at low temperature consist of nine infrared-active vibrational modes. Further simulations based on hydrogen-bond isotopologues were performed to study the involvement of hydrogen bonds in the collective modes. A feature at 118.0 cm–1 mainly stems from the collective vibration of dimer hydrogen bonds (m) while features at 102.0 and 109.6 cm–1 primarily come from the collective vibrations of linear hydrogen bonds (n). The results may be useful for monitoring molecular reaction in industrial production according to the state of hydrogen bonds. [ABSTRACT FROM AUTHOR] more...

Searching the organic compound as anti‐inflammatory agent is a fruitful effort to treat inflammatory disorders such as asthma, arthritis, psoriasis, and especially cancer. These disorders can be cured by lipoxygenase (LOX) inhibitors, which have the ability to stop the development and progression of inflammation. The present research described the synthesis of fifteen new N‐alkyl/aralkyl/aryl derivatives (7 a–o) of 2‐(4‐ethyl‐5‐(1‐phenylcarbamoyl)piperidine‐4H‐1,2,4‐triazol‐3‐ylthio)acetamide by the continuous conversions of ethyl piperidine‐4‐carboxylate (a) into phenylcarbamoyl derivative (1) hydrazide (2), semicarbazide (3) and finally the N‐ethylated 5‐(1‐phenylcarbamoyl)piperidine‐1,2,4‐triazole (4). The target molecules (7 a–o) were formed by the reaction of 4 with various electrophiles (6 a–o), in methanolic potassium hydroxide. These synthetic analogues were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. The compounds 7 a–o were screened for their inhibitory potential against 15‐lipoxygenase. Compounds 7 b, 7 e, 7 c and 7 g displayed the potent inhibitory potential (IC50 17.52±0.67, 35.61±0.81, 36.24±0.83 & 36.52±0.58 μM, respectively), whereas, moderate inhibition was shown by 7 h, 7 a, 7 d with IC50 values between 42.95±0.73 to 45.67±0.75 μM, respectively. Some compounds exhibited drug‐like characteristics due to their lower cytotoxic and good ADME profiles and supported by molecular modeling studies where one of the NH groups was found engaged through hydrogen bonding with Ala672. The carbonyl group amide and Asn554 were connected by a hydrogen bond, whereas the second NH group was also linked through hydrogen bonds with Gln363. [ABSTRACT FROM AUTHOR] more...

Reconfigurable micro–nanostructures have been largely used in the development of modern photocontrol technology. In this work, a dynamically adjustable hydrogel of supramolecule structures is realized by molecule self-assembly and cross-link in microscale. Calculations based on the molecule modeling systematically illuminate the assembly process and the mechanism of the dynamically adjustable micro–nanostructure. The transmittance changes of the hydrogel, which are measured in the visible-light range before and after electric heating, show outstanding light-control function. Thus, the one-step fabrication, bio-compatibility (no initiator, cross linker, or monomer residual), and agile photocontrol application demonstrate the potential of the adjustable physically bonded hydrogel in development of low-loss and integrated dynamical light-control devices. [ABSTRACT FROM AUTHOR] more...

Pleckstrin homology domain–containing A7 (PLEKHA7) is a cytoplasmic protein at adherens junctions that has been implicated in hypertension, glaucoma, and responses to Staphylococcus aureus a-toxin. Complex formation between PLEKHA7, PDZ domain–containing 11 (PDZD11), tetraspanin 33, and the a-toxin receptor ADAM metallopeptidase domain 10 (ADAM10) promotes junctional clustering of ADAM10 and a-toxin–mediated pore formation. However, how the N-terminal region of PDZD11 interacts with the N-terminal tandem WW domains of PLEKHA7 and how this interaction promotes tetraspanin 33 binding to the WW1 domain is unclear. Here, we used site-directed mutagenesis, glutathione S-transferase pulldown experiments, immunofluorescence, molecular modeling, and docking experiments to characterize the mechanisms driving these interactions. We found that Asp-30 of WW1 and His-75 of WW2 interact through a hydrogen bond and, together with Thr-35 of WW1, form a binding pocket that accommodates a polyproline stretch within the N-terminal PDZD11 region. By strengthening the interactions of the ternary complex, the WW2 domain stabilized the WW1 domain and cooperatively promoted the interaction with PDZD11. Modeling results indicated that, in turn, PDZD11 binding induces a conformational rearrangement, which strengthens the ternary complex, and contributes to enlarging a “hydrophobic hot spot” region on the WW1 domain. The last two lipophilic residues of tetraspanin 33, Trp-283 and Tyr-282, were required for its interaction with PLEKHA7. Docking of the tetraspanin 33 C terminus revealed that it fits into the hydrophobic hot spot region of the accessible surface of WW1. We conclude that communication between the two tandem WW domains of PLEKHA7 and the PLEKHA7–PDZD11 interaction modulate the ligand-binding properties of PLEKHA7 [ABSTRACT FROM AUTHOR] more...

Here, the adsorption of impurity species from triglyceride solvent representing a model vegetable oil is studied using atomistic molecular dynamics simulations. We compare the adsorption of water, glycerol, oleic acid, monoolein, and two types of phospholipids on model silica adsorbents differing in their OH-group density, i.e. hydrogen bonding ability, quartz and cristobalite. We find that the species containing charged groups, phospholipids DOPC and DOPE, adsorb significantly stronger than the nonionic impurities. Secondary contribution to adsorption arises from hydrogen bonding capability of the impurity species, the silica surface, and also the triglyceride solvent: in general, more hydrogen bonding sites in impurity species leads to enhanced adsorption but hydrogen bonding with solvent competes for the available sites. Interestingly, adsorption is weaker on cristobalite even though it has a higher hydrogen bonding site density than quartz. This is because the hydrogen bonds can saturate each other on the adsorbent. The finding demonstrates that optimal adsorption response is obtained with intermediate adsorbent hydrogen bonding site densities. Additionally, we find that monoolein and oleic acid show a concentration driven adsorption response and reverse micelle like aggregate formation in bulk triglyceride solvent even in the absence of water. The findings offer insight into adsorption phenomena at inorganic adsorbent - apolar solvent interfaces and provide guidelines for enhanced design of adsorbent materials for example for vegetable oil purification. [ABSTRACT FROM AUTHOR] more...

To investigate the thermal behavior of complex model with amorphous region and crystallization region of cellulose II, the structures and properties of cellulose II, amorphous chain and their combined models were studied by molecular dynamics simulation. The results showed that the amorphous chain is more susceptible to temperature than the cellulose II. It can form anti-parallel structure similar to cellulose II at high temperature. In the complex model, one end of the amorphous chain is fixed to form hydrogen bonds with the cellulose II, and the other end is not. At 300 K, the free part of amorphous chain is approximately perpendicular to the axial direction of the cellulose II. When the temperature increases, the free part of amorphous chain adheres to the surface of cellulose II. The free part of amorphous chain did not form hydrogen bond with the cellulose II. The formation of amorphous chain and surface of the cellulose II is a zipper process at 450 K. Furthermore, water molecules penetrate into the inter-space of the amorphous and crystalline regions. The probability of hydrogen bonds between water molecules and the complex model was less than 8.21% which explains why cellulose is insoluble in water. These conclusions provide a guiding significance for the dissolution mechanism of cellulose. The thermal behavior of cellulose II, amorphous chain, and their combined model with amorphous region and crystallization region were studied by molecular dynamics simulation. The results indicate that the amorphous chain can fold itself into anti-parallel structure similar to cellulose II at high temperature, and the amorphous chain attaches to the surface of the cellulose II of complex model in a zipper folding process at 450 K. It is difficult for water molecules to form hydrogen bonds with the complex, and water molecules exists mainly in the form of permeation in the interspace between the amorphous and crystalline regions [ABSTRACT FROM AUTHOR] more...

A preliminary discussion of the general problem of localization of wave functions, and the way it is approached in theoretical condensed matter physics (Wannier functions) and theoretical chemistry (localized or fragment orbitals) is followed by an application of the ideas of Paper II in this series to the structures of hydrogen as they evolve under increasing pressure. The idea that emerges is that of simultaneously operative physical (reduction of available space by an increasingly stiff wall of neighboring molecules) and chemical (depopulation of the σg bonding molecular orbital of H2, and population of the antibonding σu* MO) factors. The two effects work in the same direction of reducing the intermolecular separation as the pressure increases, but compete, working in opposite directions, in their effect on the intramolecular (nearest neighbor, intra-pair) distance. We examine the population of σg and σu* MOs in our numerical laboratory, as well as the total electron transfer (small), and polarization (moderate, where allowed by symmetry) of the component H2 molecules. From a molecular model of two interacting H2 molecules we find a linear relationship between the electron transfer from σg to σu* of a hydrogen molecular fragment and the intramolecular H-H separation, and that, in turn, allows us to estimate the expected bond lengths in H2 under pressure if the first effect (that of simple confinement) was absent. In essence, the intramolecular H-H separations under pressure are much shorter than they would be, were there no physical/confinement effect. We then use this knowledge to understand how the separate E and PV terms contribute to hydrogen phase changes with increasing pressure. [ABSTRACT FROM AUTHOR] more...

In order to explain the intricate dance of intramolecular (intra-proton-pair) H-H separations observed in a numerical laboratory of calculationally preferred static hydrogen structures under pressure, we examine two effects through discrete molecular models. The first effect, we call it physical, is of simple confinement. We review a salient model already in the literature, that of LeSar and Herschbach, of a hydrogen molecule in a spheroidal cavity. As a complement, we also study a hydrogen molecule confined along a line between two helium atoms. As the size of the cavity/confining distance decreases (a surrogate for increasing pressure), in both models the equilibrium proton separation decreases and the force constant of the stretching vibration increases. The second effect, which is an orbital or chemical factor, emerges from the electronic structure of the known molecular transition metal complexes of dihydrogen. In these the H-H bond is significantly elongated (and the vibron much decreased in frequency) as a result of depopulation of the σg bonding molecular orbital of H2, and population of the antibonding σu* MO. The general phenomenon, long known in chemistry, is analyzed through a specific molecular model of three hydrogen molecules interacting in a ring, a motif found in some candidate structures for dense hydrogen. [ABSTRACT FROM AUTHOR] more...

The crystal structure of NH4+OOH- is determined from single-crystal x-ray data obtained at 150 K. The crystal belongs to the space group P21/c and has four molecules in a unit cell. The structure consists of discrete NH4+ and OOH- ions. The OOH- ions are linked by short hydrogen bonds (2.533 Å) to form parallel infinite chains. The ammonium ions form links between these chains (the N...O distances vary from 2.714 to 2.855 Å) giving a three-dimensional network. The harmonic IR spectrum and H-bond energies are computed at the Perdew-Burke-Ernzerhof (PBE)/6-31G** level with periodic boundary conditions. A detailed analysis of the shared (bridging) protons' dynamics is obtained from the CPMD simulations at different temperatures. PBE functional with plane-wave basis set (110 Ry) is used. At 10 K the shared proton sits near the oxygen atom, only a few proton jumps along the chain are detected at 70 K while at 270 K numerous proton jumps exist in the trajectory. The local-minimum structure of the space group Cc is localized. It appears as a result of proton transfer along a chain. This process is endothermic (∼2 kJ/mol) and is described as P21/c↔2Cc. The computed IR spectrum at 10 K is close to the harmonic one, the numerous bands appear at 70 K while at 270 K it shows a very broad absorption band that covers frequencies from about 1000 to 3000 cm-1. The advantages of the NH4+OOH- crystal as a promising model for the experimental and DFT based molecular dynamics simulation studies of proton transfer along the chain are discussed. [ABSTRACT FROM AUTHOR] more...

Rotational diffusion in liquid acetonitrile, dimethylsulphoxide (DMSO), water, and methanol is studied with molecular dynamics simulations. The effects of hydrogen bonding and local dipole-dipole correlations (Kirkwood g-factor) on the relationship between the single molecule and collective relaxation are examined. The first rank single molecule dipole moment autocorrelation functions (ACFs) are constructed in the molecule-fixed coordinate frame and the principal components of rotation diffusion tensor are reported. Higher rank orientational ACFs are computed. These ACFs, as a rule, are strongly nonexponential (at least not single exponential) at longer times and the decomposition of these functions into a series of single exponentials results in broad distributions of relaxation times, with the broadening being particularly prominent in the case of higher rank ACFs. The rank dependence of characteristic times calculated as weighted averages over the relaxation time distributions does not follow the pattern of small angle (Debye) diffusion model for all liquids studied in this work except methanol. In contradiction, the same rank dependence computed by direct integration of ACFs leads to good agreement with the Debye diffusion model in the case of acetonitrile, DMSO, and water (but not methanol). The linear-angular momentum cross correlation functions are also computed and the effect of rototranslational coupling on reorientaional relaxation at longer times (>1.0 ps) is found to be small. [ABSTRACT FROM AUTHOR] more...

Molecular dynamics simulations of surface tensions of short flexible Lennard-Jones chains, composed of 2, 3, 4, and 5 segments, have been performed in this work. Using the simulation results, it is shown that the reduced surface tension depends only on the chain length and the reduced temperature. As a consequence, simple three parameters corresponding states using the acentric factor is shown to yield an excellent estimation of the reduced surface tension of the flexible Lennard-Jones chain fluid model. In addition, it has been noticed that the reduced surface tension of this fluid model is a unique function of the coexisting liquid and vapor reduced densities (i.e., there exist a universal Parachor behavior) for all chain lengths tested. When applied to real fluids, this universal behavior holds rather well for a large class of real species which can be nonspherical, nonlinear, and even polar. Only the surface tension of hydrogen-bonding compounds seems to largely deviate from this universal Parachor behavior. These interesting features of the surface tension, written in appropriate scaled forms, can probably be used to improve molecular models, in particular, those on which modern molecular based equations of state rely on. [ABSTRACT FROM AUTHOR] more...

The present study is aimed at a detailed analysis of supercritical water structure based on the combination of experimental vibrational spectra as well as molecular modeling calculations of isolated water clusters. We propose an equilibrium cluster composition model where supercritical water is considered as an ideal mixture of small water clusters (n=1–3) at the chemical equilibrium and the vibrational spectra are expected to result from the superposition of the spectra of the individual clusters, Thus, it was possible to extract from the decomposition of the midinfrared spectra the evolution of the partition of clusters in supercritical water as a function of density. The cluster composition predicted by this model was found to be quantitatively consistent with the near infrared and Raman spectra of supercritical water analyzed using the same procedure. We emphasize that such methodology could be applied to determine the portion of cluster in water in a wider thermodynamic range as well as in more complex aqueous supercritical solutions. [ABSTRACT FROM AUTHOR] more...

We present the evolution of current-voltage characteristics measured on linear fragments of deoxyribonucleic acid (DNA) molecules as a function of their length. The nonlinear behavior systematically observed at room temperature and also reported on circular plasmids suggests that the more molecules are involved in the conduction process, the higher are the current values measured. At the same time, a characteristic steplike feature superimposed to an overall increasing background appears more pronounced. We interpret this behavior in terms of simultaneous coherent and incoherent transport processes, the former taking place inside the DNA molecule, the latter through the network of molecules. Following our previous analysis on circular molecules, a phenomenological model is developed, in which a tunneling current with an energy dependent transmission coefficient is superimposed to a hopping current. The model provides a semiquantitative evidence that the steplike feature represents the signature of charge transmission inside the molecule. Our results are consistent with many of the conductivity data present in the literature. [ABSTRACT FROM AUTHOR] more...

Sum frequency generation vibrational spectra of the water molecules at the NaF and KF aqueous solution surfaces showed significantly different spectral features and different concentration dependence. This result is the first direct observation of the cation effects of the simple alkali cations, which have been believed to be depleted from the aqueous surface, on the hydrogen bonding structure of the water molecules at the electrolyte solution surfaces. These observations may provide important clues to understand the fundamental phenomenon of ions at the air/water interface. [ABSTRACT FROM AUTHOR] more...

A statistical model for water is studied, where the molecules are represented by trimers in a triangular lattice. Each atom of a water molecule occupies a single site on the lattice, and the HOH bond angle is assumed to be 120°. The molecules can interact via three different potentials: the excluded volume interaction, which prevents two molecules from occupying the same atom site, an attractive potential between any two nearest-neighbor atoms belonging to different molecules (the van der Waals interaction), and the hydrogen bond interaction, which occurs only for a particular orientation and displacement of a pair of molecules. The model is investigated by means of Monte Carlo simulations in the canonical and grand canonical ensembles. The Metropolis and the entropic sampling algorithms are used to obtain the thermodynamics of the system. We find that the entropic sampling prescription is the most efficient algorithm of them, providing information about the entropy and free energy of the system in a straightforward way. The curves for the polarization, number of hydrogen bonds, specific heat, and cumulant of energy were obtained as a function of the temperature and total concentration. In addition, the entropy of the noninteracting version of the model is compared to that of the angular trimers in a square lattice and triangles in a triangular lattice. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR] more...

P2X receptors are trimeric ATP-gated ion channels. In response to ATP binding, conformational changes lead to opening of the channel and ion flow. Current flow can decline during continued ATP binding in a process called desensitisation. The rate and extent of desensitisation is affected by multiple factors, for instance the T18A mutation in P2X2 makes the ion channel fast desensitising. We have used this mutation to investigate whether the gate restricting ion flow is different in the desensitised and the closed state, by combining molecular modelling and cysteine modification using MTSET (2-(Trimethylammonium)ethyl methanethiosulfonate). Homology modelling of the P2X2 receptor and negative space imaging of the channel suggested a movement of the restriction gate with residue T335 being solvent accessible in the desensitised, but not the closed state. This was confirmed experimentally by probing the accessibility of T335C in the P2X2 T18A/T335C (fast desensitisation) and T335C (slow desensitisation) mutants with MTSET which demonstrates that the barrier to ion flow is different in the closed and the desensitised states. To investigate the T18A induced switch in desensitisation we compared molecular dynamics simulations of the wild type and T18A P2X2 receptor which suggest that the differences in time course of desensitisation are due to structural destabilization of a hydrogen bond network of conserved residues in the proximity of T18. Image 1 • Ionic gate controls current flow in closed state, gate opens when ATP binds. • MTSET labelling suggests desensitisation gate in different place than closed state. • T18A affects desensitisation by disrupting a conserved hydrogen bond network. [ABSTRACT FROM AUTHOR] more...

The pupylation pathway marks proteins for prokaryotic ubiquitin-like protein (Pup)-proteasomal degradation and survival strategy of mycobacteria inside of the host macrophages. Deamidase of Pup (Dop) plays a central role in the pupylation pathway. It is still a matter of investigation to know the function of Dop in virulence of mycobacterial lineage. Hence, the present study was intended to describe the sequence–structure–function–virulence link of Dop for understanding the molecular virulence mechanism of Mycobacterium tuberculosis H37Rv (Mtb). Phylogenetic analysis of this study indicated that Dop has extensively diverged across the proteasome-harboring bacteria. The functional part of Dop was converged across the pathogenic mycobacterial lineage. The genome-wide analysis pointed out that the pupylation gene locus was identical to each other, but its genome neighborhood differed from species to species. Molecular modeling and dynamic studies proved that the predicted structure of Mtb Dop was energetically stable and low conformational freedom. Moreover, evolutionary constraints in Mtb Dop were intensively analyzed for inferring its sequence–structure–function relationships for the full virulence of Mtb. It indicated that evolutionary optimization was extensively required to stabilize its local structural environment at the side chains of mutable residues. The sequence–structure–function–virulence link of Dop might have retained in Mtb by reordering hydrophobic and hydrogen bonding patterns in the local structural environment. Thus, the results of our study provide a quest to understand the molecular virulence and pathogenesis mechanisms of Mtb during the infection process. [ABSTRACT FROM AUTHOR] more...

This article is a review of the current state of knowledge about the so-called charge-inverted hydrogen bond—the type of interaction proposed 10 years ago. Numerous examples of model dimers and molecules in which this type of interaction exists in the inter- and intramolecular forms, respectively, as well as systems actually existing and studied by experimental and theoretical methods will be presented. The results of extensive theoretical research on the physical nature of charge-inverted hydrogen bonds will be thoroughly discussed. Dimers with a recently described hydride-carbene bond, i.e., a particular case of charge-inverted hydrogen bond in which the carbene carbon atom plays the role of an atom with the electron lone-pair vacancy, will also be presented. [ABSTRACT FROM AUTHOR] more...

Empirical potential structure refinements have been made to recent high-energy x-ray diffraction data, providing molecular models of deeply supercooled water. The average O-O coordination number is found to drop from 5.13 at 293 K to 4.85 at 244 K, within 3.5 Å. Triplet O-O-O bond angle distributions reveal a broad peak centred at 96.4° at 293 K which shifts to 100.0° at 244 K, indicative of the local geometry becoming increasingly tetrahedral with decreasing temperature. However, although the number of non-bonded interstitial molecules between the first and second shells is depleted upon cooling, the number of interstitial molecules forming triplets that are embedded within the hydrogen bonded tetrahedral network at θOOO = 53°, remains constant. This is consistent with previous observations of an invariant O-O coordination number with temperature (4.24 out to 3.3 Å) and corresponds to non-bonded molecules positioned at close to half the ideal tetrahedral angle. Both -O-O-O- and hydrogen-bonded -O-H-O- ring length distributions show increases in 6 and 7-membered rings upon supercooling. This is concomitant with a shift and increase in intensity of peaks at r4 ∼8.7 Å and r5 ∼10.8 Å in the oxygen-oxygen pair distribution function, which in the models correspond to correlations between adjacent and next-nearest-neighbour hydrogen-bonded rings. [ABSTRACT FROM AUTHOR] more...

The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and various resting voltage sensor structures. Using molecular dynamics (MD) simulations, the capacity of the models to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor–pore domain interactions were validated. Rosetta energy calculations were applied to assess the utility of each model in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 experimentally characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants exhibited no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural basis for KCNQ1 function and can be used to generate hypotheses to explain KCNQ1 dysfunction. [ABSTRACT FROM AUTHOR] more...

Abstract The environmental impact of chemical applications can be reduced by using novel solvents with green properties. In this field, Deep Eutectic Solvents (DESs) are promising liquids thanks to their low toxicity, high eco-compatibility and high easiness and "greenness" of preparation. DESs are mixtures of a hydrogen bond donor molecule (HBD) and a hydrogen bond acceptor molecule (HBA) at the proper molar ratio. In this paper, we present the preparation of novel hydrophobic deep eutectic solvents and the studies of their properties: density, eutectic profiles, ranges of water separation, contamination of the separated phases, extraction capabilities of phenol model polluting molecules, capabilities of extraction at acidic and basic conditions. Interesting results emerged about the role of the components of the DESs because of the use of a properly-chosen set of liquids. Their capabilities were dependent on the nature of the HBD molecule, and in particular on its hydrophobicity. Even the DESs with highly water-soluble HBA showed to be easily separable from water and really efficacious as extracting agents when prepared with hydrophobic HBDs. The results of the extractions of pollutants in acid and basic conditions showed the capability of water separation and extraction efficiency of these mixtures even with water at pH = 2 and pH = 9; therefore, the phenols could interact with these liquids without involvement of any acid/base-type of interactions. Graphical abstract Unlabelled Image Highlights • Novel hydrophobic Deep Eutectic Solvents (DESs) are presented. • Studies on the role of the components showed that the hydrophobicity of the hydrogen bond donor to be fundamental. • The hydrophobicity of hydrogen bond donor has an important role in determining water separation and contamination. • The DESs with hydrophilic hydrogen bond acceptor can be separated from water, and the separation could be considered modular. • The DESs can efficaciously extract phenols and a dye from water with a simple and fast procedure, even at acid or basic pH. [ABSTRACT FROM AUTHOR] more...

Abstract Numerous microscopic definitions of hydrogen bonding have been proposed and employed in molecular simulations. They are typically based on various energetic, topological, and geometric criteria and require a specification of the cut-off values. The cut-off values are chosen to yield a reasonable description of hydrogen bonding in a particular molecular system under particular conditions and for a particular molecular model, and they are not thus straightforwardly transferable to different molecular systems or conditions. We propose a general approach to define and quantify the intermolecular bonds in liquids and solutions, including hydrogen bonds, which is free of any cutoff values. The approach is based on finding a continuous bond region in the surroundings of a local maximum of a spatial distribution function, enclosed by an isosurface going through the nearest significant saddle point. Moreover, the general definition of intermolecular bonding can quantify significance of particular intermolecular bonds or can be used locally to quantify and characterise bonds in heterogeneous systems or confinement. Besides the general definition of the intermolecular bonding, the bond region can be further characterised by a number of relevant properties such as the number of bonds per molecule, volume of a bond region per molecule, bond stability/strength or hydration number to provide deep insight into the intermolecular bonding. The approach is demonstrated for pure water and aqueous NaCl solutions under different thermodynamic conditions, and our results on the behaviour and quantification of their intermolecular bonding are compared with results obtained using commonly-used bond definitions. Graphical Abstract Highlights • A general definition of hydrogen bonding useful under various conditions. • Hydrogen bonds defined based on saddle points in spatial distribution functions. • The definition provides quantitative characteristics of the liquid structure. [ABSTRACT FROM AUTHOR] more...

In previous literature, it was found that the activity of New Delhi Metallo-β-lactamase-1 (NDM-1) was inhibited by 2,6-dipicolinic acid (DPA) derivatives. To identify the mechanism of interaction between the inhibitors and NDM-1, molecular dynamics simulations were performed for the complex systems. Via the molecular modelling, inhibitors were found to be able bind to the region of catalytic activity of NDM-1. However, the detailed binding sites of the inhibitors differed with their structures. It was determined that His189, Lys211, Met248, Ser249, His250, and Ser251 are key residues for the binding of inhibitor 36 with NDM-1, and Asp124 is the only critical residue in the NDM-1-DPA complex. Furthermore, because of the interaction of the benzene ring in inhibitor 36 with the side chain of Lys211, inhibitor 36 can form 4 strong hydrogen bonds with protein. For the NDM-1-DPA complex, owing to the absence of the aniline group, DPA can only form a weak interaction with the residues around the binding site of NDM-1, except for Asp124, leading to a weaker inhibitory activity. Therefore, we believe that the strong interaction of the inhibitor with Lys211 results in effective inhibition, and the aniline group is the element required for the inhibitory activity. [ABSTRACT FROM AUTHOR] more...

Designing of new potential specific inhibitors for CDK4 is very important in cancer therapy. The imperative features that can inhibit CDK4 were identified and refined by docking under standard precision mode, extra precision mode, extra precision mode with core constraints, and induced fit using extra precision protocol. Statistically significant correlation was observed when docking experiments in the extra precision mode carried out by applying core constraints in the ligand molecule which forms two specific hydrogen bonds with Val 96 of CDK4. Importance of solvent molecule was understood by molecular dynamic simulation studies. The presence of a water molecule which forms a hydrogen bond with Asp158 increased the binding affinity between the ligand and CDK4. Hydrogen bonding interactions, pi–pi stacking interactions, and salt bridge formation were the key interactions contributing to the increased inhibitory value. All these findings were supported by the high correlation between pIC50 and glide emodel values. Binding energy determinations under various conditions also support these findings. Thus, extra precision docking with ligand constraints through the insertion of water molecule effectively classified the actives and inactives of given set of molecules and can be used for virtual screening of new molecules for promising biological activity. Various molecular docking studies as well as binding energy calculations provide worthy insight to improve the scoring functions by adopting a suitable procedure for the target protein CDK4. It was found that extra precision flexible ligand docking under constraints with CDK4 protein, with a water molecule incorporated near the Asp158 residue as the best docking protocol. [ABSTRACT FROM AUTHOR] more...

Abstract In our recent article, we had a successful experience in applying binuclear chromium (III) model ([Cr 2 F(tBuCO 2) 2 (H 2 O) 2 (OH) 4 ]−1) instead of real chromium-wheel host complex ([Cr 8 F 8 (tBuCO 2) 16 ]) to calculate the effect of bridged-ligands substitution on the exchange coupling constants (J) values of the complexes. In this work our experienced procedure was used to evaluate the effect of pivalate (tBuCO 2) ligands substitution on the J values of the complexes. For this, at first two new groups of complexes were designed based on the replacement of pivalate by X-tBuCO 2 and X-iPrCO 2 anionic ligands (where X represents F, Cl, Br and I halogens) and then their J values were calculated. Since the existence of two halogen atoms in the structures of complexes leads to form different conformers, at first step a conformational analysis was carried out to identify the stable conformers of each complex. In X-tBuCO 2 -containing complexes four stable conformers were recognized, while X-iPrCO 2 -containing complexes had three stable conformers. At next step the J values of each of these conformers were calculated for all complexes. It was found that depending on which conformer was formed, the effect of these substitutions in each complex could be different, leading to a decrease or increase in the antiferromagnetic property of the complex. In both types of complexes, the formation of the least stable conformer, Conf1, led to the strengthening of the antiferromagnetic property of the complex but the impacts of the substitutions in other conformers were diverse. These new designed complexes could be considered as novel synthetic targets with different magnetic properties. Graphical abstract Image 1 Highlights • The effects of pivalate ligands substitutions on the magnetic properties of the Chromium-Wheel host complexes have been investigated. • An established 1-negative charged binuclear chromium (III) complex as model of the [Cr 8 F 8 (tBuCO 2) 16 ] host complexes was utilized. • It was found that, X-tBuCO 2 -containing complexes had four stable conformers, while in X-iPrCO 2 -containing complexes three stable conformers were identified. • In X-tBuCO 2 -containing complexes, if the least stable conformer, i.e. Conf1 , was formed, the antiferromagnetic property of the complex would strengthen. • Substitution of pivalate ligands by X-iPrCO 2 ligands, depending on conformer kind, could strengthen or weaken the antiferromagnetic property of the complex. [ABSTRACT FROM AUTHOR] more...

Abstract In this paper, brilliant cresyl blue (BCB) was selected as a sonosensitizer. The sonodynamic damage to human serum albumin (HSA) in the presence of BCB and the mechanism were studied by means of fluorescence and absorption spectra. Firstly, BCB could quench the intrinsic fluorescence of HSA obviously and the quenching mechanism was static quenching due to the formation of HSA-BCB complex. The results of the displacement experiments and the molecular modeling suggested that the binding site of BCB on HSA was site I, and hydrophobic forces and hydrogen bonds played major roles in the interaction between HSA and BCB. Secondly, the damage of HSA induced by the combined effects of ultrasonic irradiation and BCB was more efficient than that only BCB or ultrasound irradiation, which confirmed that BCB had sonodynamic activity. The damage degree of HSA was positively correlated with reactive oxygen species (ROS) produced in the system, which indicated that ultrasound could activate BCB to produce ROS, and the kinds of ROS produced by the combined effects of ultrasonic irradiation and BCB were mainly hydroxyl free radical, singlet oxygen and superoxide anion radical. [ABSTRACT FROM AUTHOR] more...

Abstract Time-resolved step-scan FTIR difference spectroscopy has been used to study photosystem I (PSI) with plastoquinone-9 (PQ) and two other benzoquinones (2,6-dimethyl-1,4-benzoquinone and 2,3,5,6-tetrachloro-1,4-benzoquinone) incorporated into the A 1 binding site. By subtracting a (P700+A 1 − − P700A 1) FTIR difference spectrum for PSI with the native phylloquinone (PhQ) incorporated from corresponding spectra for PSI with different benzoquinones (BQs) incorporated, FTIR double difference spectra are produced, that display bands associated with vibrational modes of the quinones, without interference from features associated with protein vibrational modes. Molecular models for BQs involved in asymmetric hydrogen bonding were constructed and used in vibrational mode frequency calculations. The calculated data were used to aid in the interpretation and assignment of bands in the experimental spectra. We show that the calculations capture the general trends found in the experimental spectra. By comparing four different FTIR double difference spectra we are able to verify unambiguously bands associated with phyllosemiquinone in PSI at 1495 and 1415 cm−1. We also resolve a previously unrecognized band of phyllosemiquinone at 1476 cm−1 that calculations suggest is due in part to a C 4 − ⃛ O stretching mode. For PSI with PQ incorporated, calculations and experiment taken together indicate that the C 1 − ⃛ O and C 4 − ⃛ O vibrational modes of the semiquinone give rise to bands at 1487 and 1444 cm−1, respectively. This is very distinct compared to PSI with PhQ incorporated. From the calculated and experimental spectra, we show that it is possible to distinguish between two possible orientations of PQ in the A 1 protein binding site. Highlights • Photosystem I was studied using time-resolved FTIR difference spectroscopy at 77 K. • Four different benzoquinones were incorporated into the A 1 protein binding site. • Density functional theory methods were used to calculate vibrational frequencies. • Calculated normal modes were used to assign bands in the experimental spectra. [ABSTRACT FROM AUTHOR] more...

Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer’s disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC 50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent Aβ N3pE−40 -lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and h ERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer’s agents. [ABSTRACT FROM AUTHOR] more...

We developed a set of conformationally locked molecules each of which makes a single CH…O H-bond/short contact and has different electron density at the acceptor oxygen atom. The downfield shift of the 1H NMR signals due to the hydrogen involved in the CH…O H-bond varied from 0.93–1.6 ppm, and the magnitude of Δδ is in correlation with the hybridization state of the acceptor oxygen and with the CH…O H-bond strengths quantified using a computational method. [ABSTRACT FROM AUTHOR] more...

RAF kinases are a family of enzymes in the MAP kinase pathway that contribute to the development of different types of cancer. BRAF is the most important member of RAF kinases. BRAF mutations have been detected in 7% of all cancers and 66% of melanomas; as such, the FDA has approved a few BRAF inhibitor drugs to date. However, BRAF can activate CRAF leading to resistance to BRAF inhibitors. Berberine (BBR) is an alkaloid that is widely distributed in different plant species. Several studies have been carried out on the anti-cancer effects of BBR but direct targets of BBR are unknown. In this study, interactions of BBR derivatives against BRAF and CRAF kinases were modeled and predicted using an in silico-based approach. To analyze and identify the residues important in BRAF docking, we modeled interactions of ATP, the universal substrate of BRAF, and found that Lys483 and Asp594 are the most important residues involved in both ATP and BBR binding [(The average score = -11.5 kcal/mol (ATP); Range of scores = -7.78 to -9.55 kcal/mol (BBR)]. In addition to these polar residues, Trp530 and Phe583 are also applicable to the molecular docking of BRAF. We also observed that Asp593 was excluded from the enzyme cavity, while Phe594 was included inside the cavity, making the enzyme inactive. Finally, three alternatives for BBR were identified with dual RAF inhibition effects [The best scores against BRAF = -11.62 kcal/mol (BBR-7), -10.64 kcal/mol (BBR-9), and -11.01 kcal/mol (BBR-10); the best scores against CRAF = -9.68 kcal/mol (BBR-7), -9.60 kcal/mol (BBR-9), and -9.20 kcal/mol (BBR-10)]. Direct effects of BBR derivatives against BRAF and CRAF kinases had not yet been reported previously, and, thus, for the first time, we report three cycloprotoberberines as lead compounds against RAF kinases. [ABSTRACT FROM AUTHOR] more...

We computationally examined the structure of anti-tumour bicyclic hexapeptide RA-VII. This peptide adopts three conformations (confs.), A, B and C, in dimethyl sulfoxide (DMSO). Although it was experimentally reported that the structure of conf. A is important for anti-tumour activity, the dynamics of confs. A, B and C are not well known. We performed quantum chemical calculations and molecular dynamics (MD) simulations of RA-VII in DMSO. The MD simulations indicated two different local stable structures for conf. C: a structure containing a bent 18-membered ring and another structure containing a rotated peptide bond between Tyr6andd-Ala1. The root-mean-square fluctuation of the 14-membered ring for conf. A was larger than that for confs. B and C. Ala4formed intramolecular hydrogen bonds more often in conf. A than in the other conformations. A large number of hydrogen bonds and large structural fluctuations are important for the anti-tumour activity of RA-VII. Our results for the structural change of conf. C and the analysis of the dynamics for confs. A, B and C may contribute to the design of new analogues of cyclic peptides. [ABSTRACT FROM PUBLISHER] more...

Although resonance-assisted H-bonds (RAHBs) are well recognized, the role of π resonance in RAHBs is controversial, as the seemingly enhanced H-bonds in unsaturated compounds may result from the constraints imposed by the σ skeleton. Herein the block-localized wave function (BLW) method, which can derive optimal yet resonance-quenched structures with related physiochemical properties, was employed to examine the correlation between π resonance and the strength of intramolecular RAHBs. Examination of a series of paradigmatic molecules with RAHBs and their saturated analogues showed that it is inappropriate to compare a conjugated system with its saturated counterpart, as they may have quite different σ frameworks. Nevertheless, comparison between a conjugated system and its resonance-quenched (i.e., electron-localized) state, which have identical σ skeletons, shows that in all studied cases, π resonance unanimously reduces the bonding distance by 0.111-0.477 Å, strengthens the bonding by 40-56 %, and redshifts the D−H vibrational frequency by 104-628 cm−1. Furthermore, there is an excellent correlation between hydrogen-bonding strength and the classical Coulomb attraction between the hydrogen-bond donor and the acceptor, which suggests that the dominant role of the electrostatic interaction in H-bonds and RAHBs originates from the charge flow from H-bond donors to acceptors through π conjugation. [ABSTRACT FROM AUTHOR] more...

The solid-liquid equilibria phase diagrams of eight eutectic systems formed by choline chloride and fatty acids, or fatty alcohols, were measured to characterize the nonideality of the liquid phase of these systems, commonly reported in the literature as examples of type III deep eutectic solvents (DESs), and to evaluate the best modeling approaches to their description. Most of these systems are shown to present only slight deviations from ideal behavior, resulting from a fine balance of the hydrogen bonding between the hydroxyl/carboxylic groups with the chloride anion and the interactions present in the pure compounds. The phase diagrams measured were modeled with an associative equation of state (EoS) and a gE model. As an EoS, the perturbed-chain statistical associating fluid theory (PC-SAFT) was used, and this model was able to accurately describe the experimental data and to provide reliable estimates of the eutectic points using just a single binary temperature-dependent interaction parameter that often correlates with the acid/alcohol chain length. The performance of PC-SAFT was further compared with the gE model, a non-random two-liquid model (NRTL), and was found to provide a better description of the experimental data, especially for the more nonideal systems. Ultimately, the data gathered, and the molecular modeling, allowed the discussion of the behavior of fatty acids or fatty alcohols as hydrogen bond donors in choline chloride-based DESs. [ABSTRACT FROM AUTHOR] more...

The physical nature of charge-inverted hydrogen bonds in H3XH [ABSTRACT FROM AUTHOR]

Lack of naturally occurring modified nucleoside 5-taurinomethyluridine (τm5U) at the ‘wobble’ 34th position in tRNALeu causes mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The τm5U34 specifically recognizes UUG and UUA codons. Structural consequences of τm5U34 to read cognate codons have not been studied so far in detail at the atomic level. Hence, 50ns multiple molecular dynamics (MD) simulations of various anticodon stem loop (ASL) models of tRNALeu in presence and absence of τm5U34 along with UUG and UUA codons were performed to explore the dynamic behaviour of τm5U34 during codon recognition process. The MD simulation results revealed that τm5U34 recognizes G/A ending codons by ‘wobble’ as well as a novel ‘single’ hydrogen bonding interactions. RMSD and RMSF values indicate the comparative stability of the ASL models containing τm5U34 modification over the other models, lacking τm5U34. Another MD simulation study of 55S mammalian mitochondrial rRNA with tRNALeu showed crucial interactions between the A-site residues, A918, A919, G256 and codon-anticodon bases. Thus, these results could improve our understanding about the decoding efficiency of human mt tRNALeu with τm5U34 to recognize UUG and UUA codons. [ABSTRACT FROM AUTHOR] more...

Fear of a fresh infection wave and a global health issue in the ongoing COVID-19 pandemic have been rekindled by the appearance of two new novel variants BF.7 and BA.4/5 of Omicron lineages. Predictions of increased antibody evasion capabilities and transmissibility have been recognised in addition to the existing lineages (BA.1.1, BA.2, BA.2.12.1 and BA.3) as cause for worry. In comparison to Omicron, BA.4 and BF.7 share nine mutations in the spike protein, Leu371Phe, Thr376Ala, Asp405Asn, Arg408Ser, Ser446Gly, Leu452Arg, Phe486Val, Arg493Gln, Ser496Gly, whereas BF.7 contains an additional mutation, Arg346Thr, in the receptor binding domain (RBD) region. Due to the critical need for analysis and data on the BA.4 and BF.7 variants, we have computationally analyzed the interaction pattern between the Omicron, BA.4 and BF.7 RBD and angiotensin-converting enzyme 2 (ACE2) to determine the influence of these unique mutations on the structures, functions, and binding affinity of RBD towards ACE2. These analyses also allow to compare molecular models to previously reported data to evaluate the robustness of our methods for quick prediction of emerging future variants. The docking results reveal that BA.4 and BF.7 have particularly strong interactions with ACE2 when compared to Omicron, as shown by several parameters such as salt bridge, hydrogen bond, and non-bonded interactions. In addition, the estimations of binding free energy corroborated the findings further. BA.4 and BF.7 were found to bind to ACE2 with similar affinities (−72.14 and − 71.54 kcal/mol, respectively) and slightly stronger than Omicron (−70.04 kcal/mol). The differences in the binding pattern between the Omicron, BA.4 and BF.7 variant complexes indicated that the BA.4 and BF.7 RBD substitutions Asp405Asn, Ser446Gly, Leu452Arg, Phe486Val and Arg493Gln caused additional interactions with ACE2. In addition, normal mode analyses also indicate more stable conformations of BA.4 and BF.7 RBDs against human ACE2. Based on these structural and simulation analyses, we hypothesized that these changes may affect the binding affinity of BA.4 and BF.7 with ACE2. [ABSTRACT FROM AUTHOR] more...

The quantitative structure-activity relationship (QSAR) models for predicting antioxidative capacity of 21 structurally similar natural and synthetic phenolic antioxidants was considered. The one-, two- and three-descriptor QSAR models were developed. For this purpose the literature data on the vitamin C equivalent antioxidative capacity (VCEAC) values were used as experimental descriptor of antioxidative capacity. Some thermodynamic and aromaticity properties, as well as the natural bond analysis (NBO) based quantities aimed at measuring the strength of intramolecular hydrogen bonds, were used as independent variables. It was examined whether a combination of these variables can yield a mathematical function that is in good correlation with the VCEAC values. It was shown that a combination of a certain thermodynamic descriptor (related to the single proton loss electron transfer mechanism) with the NBO-based quantities results in several two-descriptor models with the correlation coefficient greater than 0.950. Thus, a significant influence of internal hydrogen bonds on the antioxidative capacity of the studied molecules was confirmed. The best correlation with the VCEAC values was achieved within a three-descriptor QSAR model. This model was obtained by including a magnetic aromaticity index. It was found that aromaticity has only secondary effects on the antioxidative capacity. [ABSTRACT FROM AUTHOR] more...

Variants in the TGFBR2 kinase domain cause several human diseases and can increase propensity for cancer. The widespread application of next generation sequencing within the setting of Individualized Medicine (IM) is increasing the rate at which TGFBR2 kinase domain variants are being identified. However, their clinical relevance is often uncertain. Consequently, we sought to evaluate the use of molecular modeling and molecular dynamics (MD) simulations for assessing the potential impact of variants within this domain. We documented the structural differences revealed by these models across 57 variants using independent MD simulations for each. Our simulations revealed various mechanisms by which variants may lead to functional alteration; some are revealed energetically, while others structurally or dynamically. We found that the ATP binding site and activation loop dynamics may be affected by variants at positions throughout the structure. This prediction cannot be made from the linear sequence alone. We present our structure-based analyses alongside those obtained using several commonly used genomics-based predictive algorithms. We believe the further mechanistic information revealed by molecular modeling will be useful in guiding the examination of clinically observed variants throughout the exome, as well as those likely to be discovered in the near future by clinical tests leveraging next-generation sequencing through IM efforts. [ABSTRACT FROM AUTHOR] more...

Peptide therapeutics has been raised as an attractive approach for the treatment of breast cancer by targeting the oncogenic protein MDM2 that inactivates p53 tumor suppressor. Here, we performed molecular design of halogen bonding orthogonal to hydrogen bonding at the complex interface of MDM2 protein with its cognate peptide ligand to improve the peptide binding affinity and specificity. Crystal structure analysis, high-level quantum chemistry (QC) calculations and combined quantum mechanics/molecular mechanics (QM/MM) modeling revealed that halogen substitution at position 3 of the benzene moiety of peptide Phe3 residue can constitute a putative halogen bonding, which is shown to be geometrically perpendicular to and energetically independent of a native hydrogen bonding that share a common carbonyl oxygen acceptor. The designed halogen bonding was then validated by surface plasmon resonance (SPR) assays, that is, substitution with bromine at position 3 can considerably improve peptide affinity by ∼4-fold, but the peptide binding does not change substantially upon the bromine substitution at other positions of the Phe3 benzene moiety (the negative controls that are theoretically unable to form the halogen bonding), indicating that the orthogonal molecular interaction (OMI) system between the designed halogen bonding and native hydrogen bonding can co-work well at the complex interface of MDM2 protein with its halogenated peptide ligands. [ABSTRACT FROM AUTHOR] more...

In this study, a concise synthetic method of psammaplin A was achieved from 3-bromo-4-hydroxybenzaldahyde and hydantoin through a four-step synthesis via Knoevenagel condensation, hydrolysis, oximation and amidation in 37% overall yield. A collection of novel psammaplin A analogs focused on the variations of substituents at the benzene ring and modifications at the oxime moiety were synthesized. Among all the synthesized compounds, 5d and 5e showed better HDAC inhibition than psammaplin A and comparable cytotoxicity against four cancer cell lines (PC-3, MCF-7, A549 and HL-60). Molecular docking and dynamics simulation revealed that (i) hydrogen atom of the oxime group interacts with Asp99 of HDAC1 through a water bridged hydrogen bond and (ii) a hydroxyl group is optimal attached on the para -position of benzene, interacting with Glu203 at the entrance to the active site tunnel. [ABSTRACT FROM AUTHOR] more...

The present study reports the synthesis of molecularly imprinted chitosan-based adsorbents using 4-hydroxy benzoic acid (4HBA) as a dummy template for the selective extraction and analysis of salicylic acid (SA) using suspension polymerization method. Dummy template strategy is useful when templates like salicylic acid exhibit intramolecular hydrogen bonding. The synthesized adsorbents were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron micrograph (SEM). The adsorption capacity of the adsorbents was investigated as a function of time, concentration of analyte and mass of adsorbent employed and was found to be 500.96 μmol g-1 for the chitosan-based 4-hydroxy benzoic acid molecularly imprinted polymer (4HBACTSMIP), 221.2 μmol g-1 for the salicylic acid MIP (SACTSMIP), 220 μmol g-1 for the non-imprinted polymer (NIP), 149.7 μmol g-1 for chitosan (CTS) and 60.63 μmol g-1 for the granular activated carbon (GAC). The specific binding capacity of 4HBACTSMIP for salicylic acid was found to be 280.96 μmol g-1. The change in the Gibbs free energy (ΔG) for the template-monomer complexes formed between the templates and the functional monomer was computed using density functional theory (DFT) to interpret the nature of the interactions between them and to compare their stabilities. A systematic investigation of the molecular recognition abilities of the synthesized adsorbents was carried out using Freundlich (F) adsorption isotherm model. The binding parameters obtained from the F model demonstrate that 4HBACTSMIP exhibited higher specific molecular recognition ability towards salicylic acid. The adsorption ability of SACSTMIP was same as that of NIP due to intramolecular hydrogen bonding present in salicylic acid molecule leading to low imprinting effect. The results are supported by molecular modeling studies and the selectivity studies. [ABSTRACT FROM AUTHOR] more...

The axial modulus of the cellulose Iβ crystal is as high as 120-160 GPa. The importance of hydrogen bonds is often emphasized in this context, although intrinsic stiffness of the hydrogen bonds is relatively low. Here, hydrogen bond-covalent bond synergies are investigated quantitatively using molecular mechanics and molecular dynamics simulations for the so-called leverage effect, a model introduced recently in which strains for intra-molecular hydrogen bonds are higher than for the cellulose chain as a whole, thereby amplifying their contribution to the total stiffness. The present work also includes simulation of the hydrogen bonding band shifts in vibrational spectra during cellulose deformation, which are compared with FT-IR data. The leverage effect hypothesis was supported by the results, although the total contribution to cellulose stiffness is only 12 %. Hydrogen bonding is still critically important and would lower the modulus much more than 12 %, if 'artificially' removed in the model. The reason is that intra-molecular hydrogen bonding preserves the crystal structure and directs axial deformation mechanisms towards higher energy deformation and high stiffness. [ABSTRACT FROM AUTHOR] more...