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.
Vitamin C is one of the most abundant exogenous antioxidants in the cell, and it is of the utmost importance to elucidate its mechanism of action against radicals. In this study, the reactivity of vitamin C toward OH and \( {HO}_2/{O}_2^{-} \) radicals in aqueous medium was analyzed by ab initio molecular dynamics using CPMD code. The simulations led to results similar to those of static studies or experiments for the pair of \( {HO}_2/{O}_2^{-} \) radicals but bring new insights for the reactivity with hydroxyl radical: the reaction takes place before the formation of an adduct and consists of two steps: first an electron is transferred to hydroxyl radical and then the ascorbyl radical loses a proton.
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.
Development of new energetic salts is the key factor in replacing low performance compounds in conventional formulations of high explosives as well as propellants. Ten salts based on the nitroformate anion and various nitrogen-rich cations were designed and their geometric optimizations carried out using the density functional method. With reasonable oxygen balance (from ?36 % to 0 %), heats of formation (47–624 kJ mol?1) and high densities (1.81–1.89 g cm?3), the detonation velocity (D) and pressure (P) values of salts were calculated as 8.62–9.36 km s?1 and 33.10–40.01 GPa, respectively. Lastly, the nitroformate salts studied in this work are of prospective interest as high performance explosives.
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.
A new compound based on the D-π-A concept, where D = dimethylamino-phenyl and A = naphthoic acid, separated by an imine motif, was designed, synthesized and characterized. The spectral, energetics, and structural characteristics of the compound were studied thoroughly theoretically by density functional theory (DFT) in the gas and aqueous phases and experimentally (steady-state absorption) in aqueous media with various degrees of polarity and hydrogen bonding ability. This compound shows high sensitivity to the polarity, basicity and proton affinity of the environment. Based on DFT, TD-DFT and NBO analysis, the compound exists in the ground-state with both intermolecular and intramolecular hydrogen bond conformations in association with the –COOH, with latter isomer calculated to be more stable. Furthermore, structural changes via intermolecular solute–solvent interactions, dictate electronic modifications and spectral changes.
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.
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.
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 dual role of the ionic liquid 1-butyl-3-methyl-imidazolium trifluoroacetic acid ([C4mim]TFA) as an extractant for thiophene (TH) and a catalyst for the oxidation of TH was explored at the molecular level by performing density functional theory (DFT) calculations. The calculated interaction energies demonstrated why [C4mim]TFA is a better extractant for thiophene sulfone (THO2) than for TH. Two pathways were proposed for the oxidation of TH to THO2 with [C4mim]TFA acting as a catalyst. In the dominant pathway, a peracid is formed which then oxidizes TH to the sulfoxide and sulfones. The presence of [C4mim]TFA was found to greatly reduce the barrier to the oxidative desulfurization (ODS) of TH using H2O2 as an oxidant.
Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes.
The correlation between the kinetic stability of molecules against temperature and variations in their geometric structure under optical excitation is investigated by the example of different organic pheromone molecules sensitive to temperature or ultraviolet radiation using the density functional theory. The kinetic stability is determined by the previously developed method based on the calculation of the probability of extension of any structural bond by a value exceeding the limit value Lмах corresponding to the breaking of the bond under temperature excitation. The kinetic stability calculation only requires the eigenfrequencies and vibrational mode vectors in the molecule ground state to be calculated, without determining the transition states. The weakest bonds in molecules determined by the kinetic stability method are compared with the bond length variations in molecules in the excited state upon absorption of light by a molecule. Good agreement between the results obtained is demonstrated and the difference between them is discussed. The universality of formulations within both approaches used to estimate the stability of different pheromone molecules containing strained cycles and conjugated, double, and single bonds allows these approaches to be applied for studying other molecules.
The structure of a hairpin loop—in particular its large accessible surface area and its exposed hydrogen-bonding edges—facilitate an inherent possibility for interactions. Just like higher-order RNA macromolecules, pre-microRNAs possess a hairpin loop, and it plays a crucial role in miRNA biogenesis. Upon inspecting the crystal structures of RNAs with various functions, we noticed that, along with a fairly long double helix, the RNAs contained sequentially different hairpin loops comprising four residues. We therefore applied molecular dynamics simulation to analyze six of these previously unexplored tetraloops, along with GNRA (where N is any nucleotide and R is a purine nucleotide) tetraloops, to understand their structural and functional characteristics. A number of analyses quantifying loop stability by examining base–base stacking, base–sugar and base–phosphate hydrogen bonding, and backbone variability were performed. Importantly, we determined the different interbase stacking preferences of the single-stranded unpaired bases of the hairpin loops, which had not previously been quantified in any form. Furthermore, our study indicates that canonical GNRA structural properties are exhibited by some structures containing non-GNRA loop sequences.
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 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.
Efficient design of ionic compounds requires a systematic understanding of cation–anion interactions. Weakening of electrostatic attraction is essential to increase the liquid range of the ionic compound and decrease its melting point. Here, we report simulations of the closest-approach cation–anion distances in a variety of ion pairs containing the tetrakis(pentafluorophenyl)borate (TFPB–) anion. Small alkali cations (Li+, Na+) penetrate the TFPB– core, whereas K+ and larger organic cations do not. In the latter case, the shortest possible distance from the cations to the boron atom of TFPB– ranges from 0.50 nm to 0.63 nm. TFPB– was shown to be substantially rigid, providing a steric hindrance to thermodynamically efficient cation–anion coordination. Our results prove that TFPB– is more efficient for electrostatic charge confinement than the tetraoctylammonium cation, whereas the perfluorophenyl group is more efficient than linear alkyl chains. These simulations will motivate development of TFPB–-based ionic liquids with low phase transition points.
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.
Ecdysone receptor (EcR) is a significant target in the identification of new environmentally friendly pesticides. There are two types of ecdysone agonists: steroidal ecdysone agonists and dibenzoylhydrazines (DBHs). In this study, various modeling methods (homology modeling, molecular docking, MD simulation, binding free energy calculation, and per-residue binding free energy decomposition) were utilized to study the different binding mechanisms of two types of ecdysone agonists. Our theoretical results indicated that the relative binding potencies of DBHs can be ranked sufficiently accurately using the MOE docking method. However, MM/PBSA calculations more accurately predicted the binding affinities between steroidal ecdysone agonists and EcR-LBD. To identify the key residues involved in ecdysone agonist binding, the binding free energy (ΔGBind) was decomposed into the energy contributions of individual residues. The results revealed that nine residues—Ile339, Thr343, Met380, Met381, Tyr403, Tyr408, Asp419, Gln503, and Asn504—determined the binding affinities of the DBHs. Glu309, Met342, Arg383, Arg387, and Leu396 were important influences on the binding affinities of the steroidal ecdysone agonists.
At high temperature, silicon oxycarbide (SiCO) exhibits excellent mechanical properties and thermal stability. The incorporation of boron in SiCO results in improved performance in creep temperatures. In this work, large-scale molecular dynamics calculations were applied to obtain amorphous SiCO structures containing boron. Phase separation of C–C, B–C and Si–O was achieved for three compositions, and silicon-centered mixed-bond tetrahedrons were reproduced successfully. As the boron content increases, the boron atoms tend to form B–C and B–Si bonds in the voids, which stretches the free carbon network in some instances, causing a increase in C–C distance. Young’s modulus remains stable at high temperature for the high-carbon case, which indicates that the free carbon network plays a critical role in the structural and thermal stability of SiBCO.
Graphical Abstract Three major typical structures in the cooling down process for silicon boron oxycarbide (Si5BC2O8). Bonds: red Si–O, blue Si–C, black C–C, green B–C, purple Si–B
Multilayer-shaped compression and slide models were employed to investigate the complex sensitive mechanisms of cocrystal explosives in response to external mechanical stimuli. Here, density functional theory (DFT) calculations implementing the generalized gradient approximation (GGA) of Perdew-Burke-Ernzerhof (PBE) with the Tkatchenko-Scheffler (TS) dispersion correction were applied to a series of cocrystal explosives: diacetone diperoxide (DADP)/1,3,5-trichloro-2,4,6-trinitrobenzene (TCTNB), DADP/1,3,5-tribromo-2,4,6-trinitrobenzene (TBTNB) and DADP/1,3,5-triiodo-2,4,6-trinitrobenzene (TITNB). The results show that the GGA-PBE-TS method is suitable for calculating these cocrystal systems. Compression and slide models illustrate well the sensitive mechanism of layer-shaped cocrystals of DADP/TCTNB and DADP/TITNB, in accordance with the results from electrostatic potentials and free space per molecule in cocrystal lattice analyses. DADP/TCTNB and DADP/TBTNB prefer sliding along a diagonal direction on the a?c face and generating strong intermolecular repulsions, compared to DADP/TITNB, which slides parallel to the b?c face. The impact sensitivity of DADP/TBTNB is predicted to be the same as that of DADP/TCTNB, and the impact sensitivity of DADP/TBTNB may be slightly more insensitive than that of DADP and much more sensitive than that of TBTNB.
