In order to reveal the mechanism of drug action and design of DNA/RNA-targeted drugs containing aromatic rings, the cooperativity effects between the intermolecular π???π and H-bonding interactions in curcumin(drug)???cytosine(DNA/RNA base)???H2O were investigated by the B3LYP-D3 and MP2(full) methods with the 6–311++G(2d,p) basis set. The π???π interaction plays an important role in stabilizing the linear ternary complexes with the cooperativity effects, and the cyclic structures suffer the anticooperativity effects. The cooperativity or anticooperativity effects are notable, which could lead to a possible significant change in drug activity. The hydration is essentially the cooperativity or anticooperativity effect. These results were confirmed by the atoms in molecules (AIM), reduced density gradient (RDG), and surface electrostatic potentials analyses. The cyclic complexes are more stable, from which it can be deduced that the drug always links with the DNA/RNA base and H2O by the π???π or H-bonding interactions, and only in this way can the drug activity be shown. Therefore, the designed DNA/RNA-targeted drugs should possess a certain number of hydrophilic groups in contact with the DNA/RNA base and H2O to reconcile drug activity by the cooperativity effect between the π???π and H-bonding interactions, as is in agreement with many of the drugs in use.
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.
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.
Magnetic shielding constants for an isolated fullerene C60, cucurbituril CB[9], and the host-guest complex C60@CB[9] were calculated as a function of separation of the monomers. Our results in the gas phase and water indicate a significant variation of the magnetic properties for all atoms of the monomers in the complex and after liberation of fullerene C60 from the interior of the CB[9] cavity. The interaction between the two monomers results in a charge transfer that collaborates with a redistribution of electron density to deshield the monomers.
In this study, the doped defects in nitromethane crystals were investigated using first-principles calculations for the first time. We introduce dopant atoms in the interstitial sites of the nitromethane lattice, aiming to study the effects of element-doping on the structural properties, electronic properties, and sensitivity characteristics. The obtained results show that doped defects obviously affect the neighboring nitromethane molecules. The modification of electronic properties shows that the band gaps are significantly influenced by doped defects. Partial density of states and population analysis further reveal the mechanism for sensitivity control of nitromethane. It is shown that the new electronic states were introduced in the forbidden bands and the doped defects resulted in charge redistributions in the systems.
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.
Density functional theory calculations were carried out to investigate the formation mechanism of the thymine-thymine (6–4) dimer ((6–4)TT), which is one of the main DNA lesions induced by ultraviolet radiation and is closely related to skin cancers. The DNA backbone was found to have nonnegligible effects on the triplet reaction pathway, particularly the reaction steps involving substantial base rotations. The mechanism for the isomerization from (6–4)TT to its Dewar valence isomer (DewarTT) was also explored, confirming the necessity of absorbing a second photon. In addition, the solvation effects were examined and showed considerable influence on the potential energy surface.
High-level ab initio calculations on the complexes between noble gas atoms (He, Ne, Ar, Kr, and Xe) and dihalogen molecules (F2, Cl2, Br2, and I2) reveal trends, both in interaction energies and the energy difference between the linear and T-shaped structures, that can be explained well in terms of dispersion interactions enhanced by polar flattening of the halogens. The partial discrepancies with experimental findings are discussed.
In this work, we demonstrate that the inclusion of long-range interactions has a significant impact on the estimation of ligand–protein binding energies. Within the scope of the electrostatically embedded adaptation of the molecular fragmentation with conjugated caps (EE-AMFCC) scheme, we unveil the role played by long-range contributions in distinct levels of quantum mechanical calculations. As a prototypical system, we consider ibuprofen coupled to the human serum albumin. In particular, we show that some relevant ligand–residue interaction energies can only be accurately captured in density functional theory (DFT) approaches when the electrostatic background is properly represented by an explicit point charge distribution.
Graphical Abstract (left) The binding site FA3/FA4 of HSA containing the attached IBU. (right) Absolute value of difference between the biding energies calculated including the electrostatic embedding and the energies calculated without the electrostatic embedding using the HF, B3LYP, CAM-B3LYP, and MP2 methodologies
The interactions of the drugs amlodipine and paroxetine, which are prescribed respectively for treatment of hypertension and depression, with the metabolizing enzyme cytochrome CYP2B4 as the drug target, have been studied by molecular dynamics (MD) simulation. Poly ethylene glycol was used to control the drugs’ interactions with each other and with the target CYP2B4. Thirteen simulation systems were carefully designed, and the results obtained from MD simulations indicated that amlodipine in the PEGylated form prescribed with paroxetine in the nonPEGylated form promotes higher cytochrome stability and causes fewer fluctuations as the drugs approach the target CYP2B4 and interact with it. The simulation results led us to hypothesize that the combination of the drugs with a specific drug ratio, as proposed in this work, manifests more effective diffusivity and less instability while metabolizing with enzyme CYP2B4. Also, the active residues in the CYP2B4 enzyme that interact with the drugs were determined by MD simulation, which were consistent with the reported experimental results.
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 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 methylxanthines have attracted interest due to the changes on their biological activities and physicochemical properties in terms of the number and position of the methyl groups present in the xanthine moiety. We report a theoretical study of the influence of the methyl substituent in the basicity and reactivity of xanthine and its methylated derivatives. Our results provide that when the xanthine increases the number of methyl substituents, the gas phase basicity increases (reactivity to proton increases), and the global hardness decreases. The result is in agreement with the maximum hardness principle (MHP) that states, “at equilibrium, chemical systems are as hard as possible” (Pearson, R.G., J. Chem. Educ., 1987, 64, 561–567, and Parr R.G., Chattaraj P.K., J. Am. Chem. Soc. 1991, 113, 1854–1855).
A perfectly planar Al13+ cluster (CI) and a quasi-planar Al13+ cluster (CII) have been found for the first time. Both clusters have a triangular core surrounded by a set of ten Al atoms in the form of a ring. These cationic clusters have substantial aromatic character. The planar CI cluster has local antiaromatic patches within global aromatic sea. It is doubly aromatic having both σ and π aromatic character. The quasi-planar CII cluster is also aromatic but it has more σ-delocalization.
The aldol reaction in the presence of L-proline acting as an organocatalyst is a well-known example of asymmetric synthesis. Many theoretical and experimental studies have been carried out to probe the mechanism of this reaction. In this work, two levels of density functional theory in the gas phase and DMSO were used to elucidate the best pathways for this reaction, with the enamine and enol considered intermediates and L-proline considered either a reactant or a facilitator. The calculations indicated that both intermediates are formed simultaneously in the reaction medium. Interestingly, the formation of the enamine intermediate predominates in DMSO at room temperature, whereas the enol becomes the predominant intermediate upon the addition of water.
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 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.
The evolution of structural properties, thermodynamics and averaged (dynamic) total hardness values as a function of the composition of binary water–organic solvents, was rationalized in view of the intermolecular interactions. The organic solvents considered were ethanol, acetonitrile, and isopropanol at 0.25, 0.5, 0.75, and 1 mass fractions, and the results were obtained using molecular dynamics simulations. The site-to-site radial distribution functions reveal a well-defined peak for the first coordination shell in all solvents. A characteristic peak of the second coordination shell exists in aqueous mixtures of acetonitrile, whereas in the water–alcohol solvents, a second peak develops with the increase in alcohol content. From the computed coordination numbers, averaged hydrogen bonds and their lifetimes, we found that water mixed with acetonitrile largely preserves its structural features and promotes the acetonitrile structuring. Both the water and alcohol structures in their mixtures are disturbed and form hydrogen bonds between molecules of different kinds. The dynamic hardness values are obtained as the average over the total hardness values of 1200 snapshots per solvent type, extracted from the equilibrium dynamics. The dynamic hardness profile has a non-linear evolution with the liquid compositions, similarly to the thermodynamic properties of these non-ideal solvents.
Graphical abstract Computed dynamic total hardness, as a function of the cosolvent mass fraction for water–ethanol (EtOH), water–isopropanol (2PrOH) and water–acetonitrile (AN)
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.
