New Bis(benzimidazole) Cations for Threading through Dibenzo-24-crown-8

We report a simple bis(benzimidazole) dication which can act as new template for threading through dibenzo-24-crown-8. The effect of the solvent and counterion on the magnitude of the binding interaction and on the hydrogen bonding array in the solid state is described

New Bis(benzimidazole) Cations for Threading through Dibenzo-24-crown-8

We report a simple bis(benzimidazole) dication which can act as new template for threading through dibenzo-24-crown-8. The effect of the solvent and counterion on the magnitude of the binding interaction and on the hydrogen bonding array in the solid state is described

New Bis(benzimidazole) Cations for Threading through Dibenzo-24-crown-8

We report a simple bis(benzimidazole) dication which can act as new template for threading through dibenzo-24-crown-8. The effect of the solvent and counterion on the magnitude of the binding interaction and on the hydrogen bonding array in the solid state is described

Computational Identification of Descriptors for Selectivity in Syngas Reactions on a Mo₂C Catalyst

A microkinetic model containing 53 elementary steps based on extensive Density Functional Theory calculations is developed to describe syngas reactions on a Mo₂C catalyst under high temperature and pressure conditions, with the aim of determining the elementary steps that control reaction selectivity. The effects of adsorbate–adsorbate interactions are found to be strong, so these interactions are described using the quasi-chemical approximation. Agreement with experimental observations of selectivity for syngas reactions at <i>P</i> = 30 bar and <i>T</i> = 573 K was found to be good without parametrizing the model in any way to the experimental reaction data. The activation energies of the elementary steps in the model were estimated using a Bronsted–Evans–Polanyi relation, and sensitivity analysis is used to examine the impact of uncertainties in this relation on the selectivity-determining steps of the reaction network. Our results are a useful example of identification of key elementary steps in a complex reaction network for the reactions available with syngas over a heterogeneous catalysis

P/N Flame Retardant Based on a Pyrimidine Ring for Improving the Flame Retardancy, Mechanical Properties, and Smoke Suppression of Epoxy Resin

A P/N flame-retardant TBD based on a pyrimidine ring was devised and developed by reacting 2,4,6-triaminopyrimidine, benzaldehyde, and 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide to create a less toxic, low-smoke, and mechanically improved the flame-retardant epoxy resin (EP). The EP modified using TBD exhibited good transparency, which was attributed to the outstanding compatibility of TBD with the EP. With a phosphorus content of only 0.65%, EP/TBD10 passed the V-0 rating of the UL-94 test, and the limited oxygen index increased from 27.1% (pure EP) to 38.1%. In the cone calorimetry test (CCT), the peak heat release rate and the total heat release decreased by 34.9 and 45.7%, respectively, compared to pure EP. In addition, the modified cured EP exhibited good mechanical properties owing to the action of rigid groups and the formation of hydrogen bonds, and the tensile strength and modulus as well as the flexural strength and modulus of the samples were improved. In the smoke density test, EP/TBD20 received the ratings of HL1 and HL2 in Ds(4) and VOF4, respectively, according to EN45545-2. All results indicate that TBD is an efficient flame retardant that can enhance the flame retardancy and mechanical properties of the curing EP and reduce its smoke density, making it suitable for use in the rail transportation industry

Maximum temperature in core area with the change of cycle times.

<p>Maximum temperature in core area with the change of cycle times.</p

A Computational Investigation of Allostery in the Catabolite Activator Protein

The catabolite activator protein is a dimer that consists of two cAMP-binding subunits, each containing a C-terminus DNA-binding module and a N-terminus ligand binding domain. The system is well-known to exhibit negative cooperativity, whereby the binding of one cAMP molecule reduces the binding affinity of the other cAMP molecule by 2 orders of magnitude, despite the large separation between the cAMP binding pockets. Here we use extensive explicit-solvent molecular dynamics simulations (135 ns) to investigate the allosteric mechanism of CAP. Six trajectories were carried out for apo, singly liganded, and doubly liganded CAP, both in the presence and absence of DNA. Thorough analyses of the dynamics through the construction of dynamical cross-correlated maps, as well as essential dynamics analyses, indicated that the system experienced a switch in motion as a result of cAMP binding, in accordance with recent NMR experiments carried out on a truncated form of the protein. Analyses of conformer structures collected from the simulations revealed a remarkable event:  the DNA-binding module was found to dissociate from the N-terminus ligand binding domain. An interesting aspect of this structural change is that it only occurred in unoccupied subunits, suggesting that the binding of cAMP provides additional stability to the system, consistent with the increase in entropy that was observed in our calculations and from isothermal titration calorimetry. Analysis of the distribution of intrinsic disorder propensities in CAP amino acid sequence using PONDR VLXT and VSL1 predictors revealed that the region connecting ligand-binding and DNA-binding domains of CAP have the potential to exhibit increased flexibility. We complemented these trajectories with free energy calculations following the MM-PBSA approach on more than 2000 snapshots that included 880 normal mode analysis. The resulting free energy differences between the singly liganded and doubly liganded states were in excellent agreement with isothermal titration calorimetry data. When the free energy calculations were carried out in the presence of DNA, we discovered that a switch in cooperativity occurred, so that the binding of the first cAMP promoted the binding of the other cAMP. The components of the free energy reveal that this effect is mainly entropic in nature, whereby the DNA reduces the degree of tightening that is observed in its absence, thereby promoting binding of the second cAMP. This finding prompted us to propose a new mechanism by which CAP triggers the transcription activation that is based on an order to disorder transition mediated by cAMP binding as well as DNA

Molecular Recognition in a Diverse Set of Protein–Ligand Interactions Studied with Molecular Dynamics Simulations and End-Point Free Energy Calculations

End-point free energy calculations using MM-GBSA and MM-PBSA provide a detailed understanding of molecular recognition in protein–ligand interactions. The binding free energy can be used to rank-order protein–ligand structures in virtual screening for compound or target identification. Here, we carry out free energy calculations for a diverse set of 11 proteins bound to 14 small molecules using extensive explicit-solvent MD simulations. The structure of these complexes was previously solved by crystallography and their binding studied with isothermal titration calorimetry (ITC) data enabling direct comparison to the MM-GBSA and MM-PBSA calculations. Four MM-GBSA and three MM-PBSA calculations reproduced the ITC free energy within 1 kcal·mol^–1 highlighting the challenges in reproducing the absolute free energy from end-point free energy calculations. MM-GBSA exhibited better rank-ordering with a Spearman <i>ρ</i> of 0.68 compared to 0.40 for MM-PBSA with dielectric constant (ε = 1). An increase in ε resulted in significantly better rank-ordering for MM-PBSA (<i>ρ</i> = 0.91 for ε = 10), but larger ε significantly reduced the contributions of electrostatics, suggesting that the improvement is due to the nonpolar and entropy components, rather than a better representation of the electrostatics. The SVRKB scoring function applied to MD snapshots resulted in excellent rank-ordering (<i>ρ</i> = 0.81). Calculations of the configurational entropy using normal-mode analysis led to free energies that correlated significantly better to the ITC free energy than the MD-based quasi-harmonic approach, but the computed entropies showed no correlation with the ITC entropy. When the adaptation energy is taken into consideration by running separate simulations for complex, apo, and ligand (MM-PBSA_ADAPT), there is less agreement with the ITC data for the individual free energies, but remarkably good rank-ordering is observed (<i>ρ</i> = 0.89). Interestingly, filtering MD snapshots by prescoring protein–ligand complexes with a machine learning-based approach (SVMSP) resulted in a significant improvement in the MM-PBSA results (ε = 1) from <i>ρ</i> = 0.40 to <i>ρ</i> = 0.81. Finally, the nonpolar components of MM-GBSA and MM-PBSA, but not the electrostatic components, showed strong correlation to the ITC free energy; the computed entropies did not correlate with the ITC entropy

A Computational Investigation of Allostery in the Catabolite Activator Protein

The catabolite activator protein is a dimer that consists of two cAMP-binding subunits, each containing a C-terminus DNA-binding module and a N-terminus ligand binding domain. The system is well-known to exhibit negative cooperativity, whereby the binding of one cAMP molecule reduces the binding affinity of the other cAMP molecule by 2 orders of magnitude, despite the large separation between the cAMP binding pockets. Here we use extensive explicit-solvent molecular dynamics simulations (135 ns) to investigate the allosteric mechanism of CAP. Six trajectories were carried out for apo, singly liganded, and doubly liganded CAP, both in the presence and absence of DNA. Thorough analyses of the dynamics through the construction of dynamical cross-correlated maps, as well as essential dynamics analyses, indicated that the system experienced a switch in motion as a result of cAMP binding, in accordance with recent NMR experiments carried out on a truncated form of the protein. Analyses of conformer structures collected from the simulations revealed a remarkable event:  the DNA-binding module was found to dissociate from the N-terminus ligand binding domain. An interesting aspect of this structural change is that it only occurred in unoccupied subunits, suggesting that the binding of cAMP provides additional stability to the system, consistent with the increase in entropy that was observed in our calculations and from isothermal titration calorimetry. Analysis of the distribution of intrinsic disorder propensities in CAP amino acid sequence using PONDR VLXT and VSL1 predictors revealed that the region connecting ligand-binding and DNA-binding domains of CAP have the potential to exhibit increased flexibility. We complemented these trajectories with free energy calculations following the MM-PBSA approach on more than 2000 snapshots that included 880 normal mode analysis. The resulting free energy differences between the singly liganded and doubly liganded states were in excellent agreement with isothermal titration calorimetry data. When the free energy calculations were carried out in the presence of DNA, we discovered that a switch in cooperativity occurred, so that the binding of the first cAMP promoted the binding of the other cAMP. The components of the free energy reveal that this effect is mainly entropic in nature, whereby the DNA reduces the degree of tightening that is observed in its absence, thereby promoting binding of the second cAMP. This finding prompted us to propose a new mechanism by which CAP triggers the transcription activation that is based on an order to disorder transition mediated by cAMP binding as well as DNA

A Computational Investigation of Allostery in the Catabolite Activator Protein

The catabolite activator protein is a dimer that consists of two cAMP-binding subunits, each containing a C-terminus DNA-binding module and a N-terminus ligand binding domain. The system is well-known to exhibit negative cooperativity, whereby the binding of one cAMP molecule reduces the binding affinity of the other cAMP molecule by 2 orders of magnitude, despite the large separation between the cAMP binding pockets. Here we use extensive explicit-solvent molecular dynamics simulations (135 ns) to investigate the allosteric mechanism of CAP. Six trajectories were carried out for apo, singly liganded, and doubly liganded CAP, both in the presence and absence of DNA. Thorough analyses of the dynamics through the construction of dynamical cross-correlated maps, as well as essential dynamics analyses, indicated that the system experienced a switch in motion as a result of cAMP binding, in accordance with recent NMR experiments carried out on a truncated form of the protein. Analyses of conformer structures collected from the simulations revealed a remarkable event:  the DNA-binding module was found to dissociate from the N-terminus ligand binding domain. An interesting aspect of this structural change is that it only occurred in unoccupied subunits, suggesting that the binding of cAMP provides additional stability to the system, consistent with the increase in entropy that was observed in our calculations and from isothermal titration calorimetry. Analysis of the distribution of intrinsic disorder propensities in CAP amino acid sequence using PONDR VLXT and VSL1 predictors revealed that the region connecting ligand-binding and DNA-binding domains of CAP have the potential to exhibit increased flexibility. We complemented these trajectories with free energy calculations following the MM-PBSA approach on more than 2000 snapshots that included 880 normal mode analysis. The resulting free energy differences between the singly liganded and doubly liganded states were in excellent agreement with isothermal titration calorimetry data. When the free energy calculations were carried out in the presence of DNA, we discovered that a switch in cooperativity occurred, so that the binding of the first cAMP promoted the binding of the other cAMP. The components of the free energy reveal that this effect is mainly entropic in nature, whereby the DNA reduces the degree of tightening that is observed in its absence, thereby promoting binding of the second cAMP. This finding prompted us to propose a new mechanism by which CAP triggers the transcription activation that is based on an order to disorder transition mediated by cAMP binding as well as DNA