Herein we report a study of the switchable [3]rotaxane reported by Huang et al. (Appl Phys Lett 85(22):5391–5393, 1) that can be mounted to a surface to form a nanomechanical, linear, molecular motor. We demonstrate the application of semiempirical electronic structure theory to predict the average and instantaneous force generated by redox-induced ring shuttling. Detailed analysis of the geometric and electronic structure of the system reveals technical considerations essential to success of the approach. The force is found to be in the 100–200 pN range, consistent with published experimental estimates.
The factors that explain the competition between intramolecular NO linkage photoisomerization and NO photorelease in five ruthenium nitrosyl complexes were investigated. By applying DFT-based methods, it was possible to characterize the ground states and lowest triplet potential energy surfaces of these species, and to establish that both photoisomerization and photorelease processes can occur in the lowest triplet state of each species. This work highlights the crucial role of the sideways-bonded isomer, a metastable state also known as the MS2 isomer, in the photochemical loss of NO, while the results obtained also indicate that the population of the triplet state of this isomer is compulsory for both processes and show how photoisomerization and photorelease interfere.
The conversion of 2-phenylbenzimidazole using o-phenylenediamine and benzaldehyde can be improved significantly under β-cyclodextrin (β-CD). The density functional theory (DFT) method was applied to study the whole process. According to energy parameters (binding energy, deformation energy) and structural deformation, entry models and the reaction process can be pinpointed, with o-phenylenediamine embedding β-CD from a wide rim, and then benzaldehyde passing into the inclusion from the narrow rim. Subsequently, natural bonding orbital (NBO), Mulliken charge, frontier orbital, FuKui function and nuclear magnetic resonance (NMR) methods were employed to reveal the mechanism of electron transfer. The results illustrate that β-CD plays a catalytic role in synthesis reaction mechanism on the secondary side, improving the reactivity and selectivity of the process.
Graphical Abstract Density functional theory study of the effects of β-cyclodextrin in synthesis of 2-phenylbenzimidazole via benzaldehyde and o-phenylenediamine
The ternary complexes ML???PyZX2???NH3 (ML?=?CuCl, CuCN, AgCN, and AuCN; Z?=?P, As, and Sb; X?=?H and F) have been investigated with quantum chemical calculations. The results showed that the existence of coordination interaction has a prominent enhancing effect on the strength of pnicogen bonding. Even in ML???PySbH2???NH3, ML???PyAsF2???NH3, and ML???PySbF2???NH3, the pnicogen bond varies from a purely closed-shell interaction to a partially covalent interaction. The coordination interaction results in the enlargement of the σ-hole on the pnicogen atom and thus the enhancement of pnicogen bonding. In addition, the contribution of orbital interaction is also important.
The absorption and emission spectra of dichlorvos and the dichlorvos-MAA complex in methanol, water, and chloroform in the molecularly imprinted recognition were investigated systematically. The M06-2X results revealed that: 1) the hydroxyl groups in polar solvents such as methanol and water may markedly influence the weak interactions, and then alter the adsorption and emission spectra; 2) the electronic excitation in absorption spectra of dichlorvos is dominated by the configuration HOMO?→?LUMO, but in the most stable dichlorvos-MAA it becomes the ππ* excitation of HOMO?→?LUMO?+?1; 3) Mulliken charges reveal that dichlorvos almost dissociates to Cl- and a cation in its S1 excitation state; 4) the phosphorescence spectra of dichlorvos-MAA are relatively weak.
Graphical Abstract The absorption and emission spectra of dichlorvos and the dichlorvos-MAA complex in the molecularly imprinted recognition of dichlorvos were investigated systematically in methanol, water, and chloroform as solvents.
An experimentally determined structure for human CYP2J2—a member of the cytochrome P450 family with significant and diverse roles across a number of tissues—does not yet exist. Our understanding of how CYP2J2 accommodates its cognate substrates and how it might be inhibited by other ligands thus relies on our ability to computationally predict such interactions using modelling techniques. In this study we present a computational investigation of the binding of arachidonic acid (AA) to CYP2J2 using homology modelling, induced fit docking (IFD) and molecular dynamics (MD) simulations. Our study reveals a catalytically competent binding mode for AA that is distinct from a recently published study that followed a different computational pipeline. Our proposed binding mode for AA is supported by crystal structures of complexes of related enzymes to inhibitors, and evolutionary conservation of a residue whose role appears essential for placing AA in the right site for catalysis.
Graphical Abstract Arachidonic acid docked in the active site of CYP2J2 assumes a catalytically competent binding mode stabilised by hydrogen bonds to Arg117
The main absorption peaks were obtained for 1-(1-hydroxy-4-methyl-2-phenylazo)-2-naphthol-4-sulfonic acid. Generalized gradient approximation, hybrid, semi-empirical, and Coulomb attenuating methods were utilized to compare theoretical electronic transitions and experimental absorption spectra at different pH. The main peaks and shoulders observed in experimental spectra were assigned to its correct conformer. In order to find the most populated conformer, thermal effects on stability calculations were investigated to obtain molar fractions of possible isomers present at room and higher temperature. Theoretical electronic transitions at distinct pH could be obtained varying the protonation a deprotonation degree. It was found that generalized gradient approximation performs very well the first transition peak at neutral pH. For higher pH, all methodologies got a bathochromic shift in agreement with experiment and finally, from these theoretical results, it was obtained that this azo dye is hardly protonated in experiments since results presented here, predict a variation of absorption spectra for all proposed methodologies when the molecule is protonated, which is different to experimental results.
In this article, we explore the capacity of formed Schiff base complexes to trap metal atoms or ions, using their aromatic ends. The intrinsic geometry of each complex defines the process of substitution. Two cases were studied; one involving a trans Schiff base complex and the other considering how a salen ligand, with nickel systems traps chromium. We also assessed the nature of the new bonds and the frontier molecular orbitals.
The anti-hypertensive drugs amlodipine, atenolol and lisinopril, in ordinary and PEGylated forms, with different combined-ratios, were studied by molecular dynamics simulations using GROMACS software. Twenty simulation systems were designed to evaluate the interactions of drug mixtures with a dimyristoylphosphatidylcholine (DMPC) lipid bilayer membrane, in the presence of water molecules. In the course of simulations, various properties of the systems were investigated, including drug location, diffusion and mass distribution in the membrane; drug orientation; the lipid chain disorder as a result of drug penetration into the DMPC membrane; the number of hydrogen bonds; and drug surface area. According to the results obtained, combined drugs penetrate deeper into the DMPC lipid bilayer membrane, and the lipid chains remain ordered. Also, the combined PEGylated drugs, at a combination ratio of 1:1:1, enhance drug penetration into the DMPC membrane, reduce drug agglomeration, orient the drug in a proper angle for easy penetration into the membrane, and decrease undesirable lipotoxicity due to distorted membrane self-assembly and thickness.
Bond critical points (BCPs) in the quantum theory of atoms in molecules (QTAIM) are shown to be a consequence of the molecular topology, symmetry, and the Poincaré-Hopf relationship, which defines the numbers of critical points of different types in a scalar field. BCPs can be induced by a polarizing field or by addition of a single non-bonded atom to a molecule. BCPs and their associated bond paths are therefore suggested not to be a suitable means of identifying chemical bonds, or even attractive intermolecular interactions.
The lateral pressure exerted on cell membrane is of great importance to signal transduction. Here, we perform molecular dynamics simulation to explore how lateral pressure affects the biophysical properties of lipid bilayer as well as nitrogen distribution in the membrane. Our results show that both physical properties of cell membrane and nitrogen distribution are highly sensitive to the lateral pressure. With the increasing lateral pressure, area per lipid drops and thickness of membrane increases obviously, while nitrogen molecules are more congested in the center of lipid bilayer than those under lower lateral pressure. These results suggest that the mechanism of nitrogen narcosis may be related to the lateral pressure.
Graphical Abstract (a) Schematic illustration of pressure exerted on the membrane. Carbon (cyan), oxygen (red), nitrogen (blue) and phosphorous (tan) in head groups are shown by using big spheres, while the lipid tails are shown as dynamicbonds. Nitrogen molecules are depicted as the yellow balls. Water molecules are omitted for clarity. (b) Probability density of the z direction of nitrogen molecules, where the z axis is normal to the lipid bilayer. The center of the lipid bilayer is fixed at z?=?0 nm
Three different pKa prediction methods were used to calculate the pKa of Lys115 in acetoacetate decarboxylase (AADase): the empirical method PROPKA, the multiconformation continuum electrostatics (MCCE) method, and the molecular dynamics/thermodynamic integration (MD/TI) method with implicit solvent. As expected, accurate pKa prediction of Lys115 depends on the protonation patterns of other ionizable groups, especially the nearby Glu76. However, since the prediction methods do not explicitly sample the protonation patterns of nearby residues, this must be done manually. When Glu76 is deprotonated, all three methods give an incorrect pKa value for Lys115. If protonated, Glu76 is used in an MD/TI calculation, the pKa of Lys115 is predicted to be 5.3, which agrees well with the experimental value of 5.9. This result agrees with previous site-directed mutagenesis studies, where the mutation of Glu76 (negative charge when deprotonated) to Gln (neutral) causes no change in Km, suggesting that Glu76 has no effect on the pKa shift of Lys115. Thus, we postulate that the pKa of Glu76 is also shifted so that Glu76 is protonated (neutral) in AADase.
In this work, through a docking analysis of compounds from the ZINC chemical library on human β-tubulin using high performance computer cluster, we report new polycyclic aromatic compounds that bind with high energy on the colchicine binding site of β-tubulin, suggesting three new key amino acids. However, molecular dynamic analysis showed low stability in the interaction between ligand and receptor. Results were confirmed experimentally in in vitro and in vivo models that suggest that molecular dynamics simulation is the best option to find new potential β-tubulin inhibitors.
Based on the structure of MOF-808, different substituents were introduced to replace hydrogen atom on the phenyl ring of MOF-808. The GCMC method was used to study the effect of functional groups on the hydrogen storage properties of MOF-808-X (X?=??OH, ?NO2, ?CH3, ?CN, ?I). The H2 uptakes and isosteric heat of adsorption were simulated at 77 K. The results indicate that all these substituents have favorable impact on the hydrogen storage capacity, and –CN is found to be the most promising substituent to improve H2 uptake. These results may be helpful for the design of MOFs with higher hydrogen storage capacity.
Graphical abstract Atomistic structures of MOFs. (a) The structures of MOF-808-X. (b) Model of organic linker. Atom color scheme: C, gray; H, white; O, red; X, palegreen (X?=??OH, ?NO2, ?CH3, ?CN, ?I)
The activation of human epidermal growth factor receptor (hEGFR) involves a large conformational change in its soluble extracellular domains (sECD, residues 1–620), from a tethered to an extended conformation upon binding of ligands, such as EGF. It has been reported that this dynamic process is pH-dependent, that is, hEGFR can be activated by EGF at high pH to form an extended dimer but remains as an inactive monomer at low pH. In this paper, we perform all-atom molecular dynamics (MD) simulations starting from the tethered conformation of sECD:EGF complex, at pH 5.0 and 8.5, respectively. Simulation results indicate that sECD:EGF shows different dynamic properties between the two pHs, and the complex may have a higher tendency of activation at pH 8.5. Twenty residues, including 13 histidines, in sECD:EGF have different protonation states between the two pHs (calculated by the H++ server). The charge distribution at pH 8.5 is more favorable for forming an extended conformation toward the active state of sECD than that at pH 5.0. Our study may shed light on the mechanism of pH dependence of hEGFR activation.
Aminopeptidase N (APN) is a zinc-dependent ectopeptidase involved in cell proliferation, secretion, invasion, and angiogenesis, and is widely recognized as an important cancer target. However, the mechanisms whereby ligands leave the active site of APN remain unknown. Investigating ligand dissociation processes is quite difficult, both in classical simulation methods and in experimental approaches. In this study, random acceleration molecular dynamics (RAMD) simulation was used to investigate the potential dissociation pathways of ligand from APN. The results revealed three pathways (channels A, B and C) for ligand release. Channel A, which matches the hypothetical channel region, was the most preferred region for bestatin to dissociate from the enzyme, and is probably the major channel for the inner bound ligand. In addition, two alternative channels (channels B and C) were shown to be possible pathways for ligand egression. Meanwhile, we identified key residues controlling the dynamic features of APN channels. Identification of the dissociation routes will provide further mechanistic insights into APN, which will benefit the development of more promising APN inhibitors.
The solubility advantage (SA) of meloxicam cocrystalized with mono- and dicarboxylic acids was expressed in terms of equilibrium constants involving active pharmaceutical ingredient and coformer in aqueous solutions. It is argued that SA can be quantified by concentration of pairs formed in water. The pH and concentration of dissolved components is included explicitly in the model. The alternative behavior of mono- and dicarboxylic acids was emphasized and addressed to different structural motifs. The structural and energetic properties of meloxicam and its complexes with carboxylic acids were characterized, including tautmerism and dissociation in aqueous media. In particular, performed in silico modeling confirmed experimental observation that meloxicam dissolved in water or modest acidic solutions is expected to be a mixture of anionic form in equilibrium with at least five neutral isomers. Tautomer-related diversity of pairs formation and the possibility of salt formation is also discussed.
Coarse-grained force field (CGFF) methods were applied to study the self-assembly of sodium dodecyl sulfate with fragrance additives. The CGFF parameters were parameterized and validated using experimental and all-atom simulation data. Direct molecular dynamics simulations were carried out to characterize the initial aggregation, partitioning of fragrances, and chemical potentials of the surfactant and fragrance molecules in aggregates of different sizes. The equilibrium critical micelle concentrations (CMCs) and micelle size distributions, which could not be obtained by direct simulation, were predicted using the calculated chemical potentials in combination with a thermodynamic model. The predicted partitioning of fragrances, CMCs, micelle sizes, and micelle structures agree well with previously reported experimental data.
