DFT and docking studies of rhodostreptomycins A and B and their interactions with solvated/nonsolvated Mg2+ and Ca2+ ions

The interactions of L-aminoglucosidic stereoisomers such as rhodostreptomycins A (Rho A) and B (Rho B) with cations (Mg²⁺, Ca²⁺, and H⁺) were studied by a quantum mechanical method that utilized DFT with B3LYP/6-311G**. Docking studies were also carried out in order to explore the surface recognition properties of L-aminoglucoside with respect to Mg²⁺ and Ca²⁺ ions under solvated and nonsolvated conditions. Although both of the stereoisomers possess similar physicochemical/antibiotic properties against Helicobacter pylori, the thermochemical values for these complexes showed that its high affinity for Mg²⁺ cations caused the hydration of Rho B. According to the results of the calculations, for Rho A–Ca²⁺(H₂O)₆, ΔH = ?72.21 kcal?mol^?1; for Rho B–Ca²⁺(H₂O)₆, ΔH = ?72.53 kcal?mol^?1; for Rho A–Mg²⁺(H₂O)₆, ΔH = ?72.99  kcal?mol^?1 and for Rho B–Mg²⁺(H₂O)₆, ΔH = ?95.00  kcal?mol^?1, confirming that Rho B binds most strongly with hydrated Mg²⁺, considering the energy associated with this binding process. This result suggests that Rho B forms a more stable complex than its isomer does with magnesium ion. Docking results show that both of these rhodostreptomycin molecules bind to solvated Ca²⁺ or Mg²⁺ through hydrogen bonding. Finally, Rho B is more stable than Rho A when protonation occurs.

Microsolvation and hydration enthalpies of CaC2O4(H2O) n (n = 0-16) and C2O4 2-(H2O) n (n = 0-14): an ab initio study

We studied hydrated calcium oxalate and its ions at the restricted Hartree–Fock RHF/6-31G* level of theory. Performing a configurational search seems to improve the fit of the HF/6-31G* level to experimental data. The first solvation shell of calcium oxalate contains 13 water molecules, while the first solvation shell of oxalate ion is formed by 14 water molecules. The first solvation shell of Ca(II) is formed by six water molecules, while the second shell contains five. At 298.15 K, we estimate the asymptotic limits (infinite dilution) of the total standard enthalpies of hydration for Ca(II), oxalate ion and calcium oxalate as ?480.78, –302.78 and –312.73 kcal mol^?1, resp. The dissociation of hydrated calcium oxalate is an endothermic process with an asymptotic limit of +470.84 kcal mol^?1.

Molecular dynamics study of Na+ transportation in a cyclic peptide nanotube and its influences on water behaviors in the tube

The dynamics of Na⁺ transportation in a transmembrane cyclic peptide nanotube of 8?×?(WL)₄/POPE has been simulated. The curve of PMF (potential of mean force) for Na⁺ moving through the tube, based on ABF (adaptive biasing force) method, indicates that Na⁺ possesses lower free energy in an α-plane region than in a mid-plane one. It was found that Na⁺ would desorb one or two water molecules in the first solvation shell when entering the tube and later maintain in a solvation state. The average numbers of water molecules around Na⁺ are 4.50, 4.09 in the first solvation shell, and 3.10, 4.08 in the second one for Na⁺ locating in an α-plane zone and a mid-plane region, respectively. However, water molecules far away from Na⁺ location still nearly arrange in a form of 1-2-1-2 file. The dipole orientations of water molecules in the regions of gaps 1 and 7 display “D-defects”, resulted from the simultaneous electrostatic potentials generated by Na⁺ and the bare carbonyls at the tube mouths. Such “D-defects” accommodate the energetically favorable water orientations thereby.

A B3LYP and MP2(full) theoretical investigation into the strength of the C-NO2 bond upon the formation of the molecule-cation interaction between Na+ and the nitro group of nitrotriazole or its methyl derivatives

The changes of bond dissociation energy (BDE) in the C–NO₂ bond and nitro group charge upon the formation of the molecule-cation interaction between Na⁺ and the nitro group of 14 kinds of nitrotriazoles or methyl derivatives were investigated using the B3LYP and MP2(full) methods with the 6-311++G**, 6-311++G(2df,2p) and aug-cc-pVTZ basis sets. The strength of the C–NO₂ bond was enhanced in comparison with that in the isolated nitrotriazole molecule upon the formation of molecule-cation interaction. The increment of the C–NO₂ bond dissociation energy (ΔBDE) correlated well with the molecule-cation interaction energy. Electron density shifts analysis showed that the electron density shifted toward the C-NO₂ bond upon complex formation, leading to the strengthened C-NO₂ bond and the possibly reduced explosive sensitivity.

Activation of the human red cell calcium ATPase by calcium pretreatment

Some kinetic parameters of the human red cell Ca²⁺-ATPase were studied on calmodulin-free membrane fragments following preincubation at 37°C. After 30 min treatment with EGTA(1 mm) plus dithioerythritol (1 mm), a V _max of about 0.4 μmol P_i/mg × hr and a K _s of 0.3 μm Ca²⁺ were found. When Mg²⁺ (10 mm) or Ca²⁺(10 μm) were also added during preincubation, V _maxbut not Kwas altered. Ca²⁺ was more effective than Mg²⁺, thus increasing V _max to about 1.3 μmol P_i/mg × hr. The presence of both Ca²⁺ and Mg²⁺ during pretreatment decreasedKto 0.15 μm, while having no apparent effect on V _max. Conversely, addition of ATP (2 mm) with either Ca²⁺ or Ca²⁺ plus Mg²⁺increased V_max without affecting K. Preincubation with Ca²⁺ for periods longer than 30 min further increased V_maxand reduced Kto levels as low as found with calmodulin treatment. The Ca²⁺ activation was not prevented by adding proteinase inhibitors (iodoacetamide, 10 mm; leupeptin, 200 μm; pepstatinA, 100 μm; phenylmethanesulfonyl fluoride, 100 μm). The electrophoretic pattern of membranes preincubated with or without Mg²⁺, Ca²⁺ or Ca²⁺ plus Mg²⁺ did not differ significantly from each other. Moreover, immunodetection of Ca²⁺-ATPase by means of polyclonal antibodiesrevealed no mobility change after the various treatments. The above stimulation was not altered by neomycin (200 μm), washing with EGTA (5 mm) or by both incubating and washing with delipidized serum albumin (1 mg/ml), or omitting dithioerythritol from the preincubation medium. On the other hand, the activation elicited by Ca²⁺ plus ATP in the presence of Mg²⁺ was reduced 25–30% by acridine orange (100 μm), compound 48/80 (100 μm) or leupeptin (200 μm) but not by dithio-bis-nitrobenzoic acid (1 mm). The fluorescence depolarization of 1,6-diphenyl-and l-(4-trimethylammonium phenyl)-6-phenyl 1,3,5-hexatriene incorporated into membrane fragments was not affected after preincubating under the different conditions. The results show that proteolysis, fatty acid production, an increased phospholipid metabolism or alteration of membrane fluidity are not involved in the Ca²⁺ effect. Ca²⁺ preincubation may stimulate the Ca²⁺-ATPase activity by stabilizing or promoting the E₁ conformation.     

Competitive blockage of the sodium channel by intracellular magnesium ions in central mammalian neurones

The aim of this study was to determine from macroscopic current analysis how intracellular magnesium ions, Mg _i ²⁺ , interfere with sodium channels of mammalian neurones. It is reported here that permeation across the sodium channel is voltage- and concentration-dependently reduced by Mg _i ²⁺ . This results in a general reduction of sodium membrane conductance and an outward sodium peak current at large positive potentials. 30 mM Mg _i ²⁺ leads to a negative shift of voltage dependence of sodium channel gating parameters, probably due to the surface potential change of the membrane. This shift alone is, however, insufficient to explain the reduction of outward sodium currents. The blockage by Mg _i ²⁺ is decreased upon increasing intracellular or extracellular Na⁺ concentration, which suggests that Mg?' interferes with sodium permeation by competitively occupying sodium channels. Using a kinetic model to describe the sodium permeation, the dissociation constant (at zero membrane potential) of Mg _i ²⁺ for the sodium channel has been calculated to be 8.65 ± 1.51 mM, with its binding site located at 0.26 ± 0.05 electrical distance from the inner membrane. This dissociation constant is smaller than that of Na _i ⁺, which is 83.76 ± 7.60 mM with its binding site located at 0.75 ± 0.23. The low dissociation constant of Mg _i ²⁺ reflects its high affinity for the sodium channel.     

Mn2+/Mg2+-dependent pyruvate kinase from a d-lactic acid-producing bacterium Sporolactobacillus inulinus: characterization of a novel Mn2+-mediated allosterically regulated enzyme

Sporolactobacillus inulinus has attracted scientific and commercial interest due to its high efficiency in d-lactic acid production. Pyruvate kinase (PYK) is one of the key regulatory points in glycolysis, and well-activated PYK can improve d-lactic acid production. A novel Mn²⁺/Mg²⁺-dependent PYK from S. inulinus was expressed in Escherichia coli and purified to homogeneity. Kinetic characterization demonstrated that the S. inulinus PYK had drastically higher activity and affinity toward substrates in the presence of Mn²⁺ compared to those of the common PYK cofactor Mg²⁺, and the circular dichroism spectra of the S. inulinus PYK suggested a Mn²⁺-mediated allosteric activation. The S. inulinus PYK was also allosterically regulated by ribose-5-phosphate or AMP activation and inorganic phosphate or ATP inhibition. The inhibition could be marked reduced or fully eliminated in the presence of activators. The result of fermentations by S. inulinus Y2-8 showed that the extracellular-added MnSO₄ and KH₂PO₄ significantly affected glycolysis flux and d-lactic acid production, which is consistent with the allosteric regulation of Mn²⁺ and inorganic phosphate on PYK. The sophisticated regulatory role of PYK would establish the foundation of substantial disturbance or restructuring of cellular metabolism for improving the S. inulinus d-lactic acid production.     

A comparative theoretical investigation into the strength of the trigger-bond in the Na+, Mg2+ and HF complexes involving the nitro group of R–NO2 (R = –CH3, –NH2 and –OCH3) or the C = C bond of (E)-O2N–CH = CH–NO2

A comparative theoretical investigation into the change in strength of the trigger-bond upon formation of the Na⁺, Mg²⁺ and HF complexes involving the nitro group of RNO₂ (R?=? –CH₃, –NH₂, –OCH₃) or the C?=?C bond of (E)-O₂N–CH?=?CH–NO₂ was carried out using the B3LYP and MP2(full) methods with the 6-311++G**, 6-311++G(2df,2p) and aug-cc-pVTZ basis sets. Except for the Mg²⁺?π system with (E)-O₂N–CH?=?CH–NO₂ (i.e., C₂H₂N₂O₄?Mg²⁺), the strength of the trigger-bond X–NO₂ (X?=?C, N or O) was enhanced upon complex formation. Furthermore, the increment of bond dissociation energy of the X–NO₂ bond in the Na⁺ complex was far greater than that in the corresponding HF system. Thus, the explosive sensitivity in the former might be lower than that in the latter. For C₂H₂N₂O₄?Mg²⁺, the explosive sensitivity might also be reduced. Therefore, it is possible that introducing cations into the structure of explosives might be more efficacious at reducing explosive sensitivity than the formation of an intermolecular hydrogen-bonded complex. AIM, NBO and electron density shifts analyses showed that the electron density shifted toward the X–NO₂ bond upon complex formation, leading to a strengthened X–NO₂ bond and possibly reduced explosive sensitivity.

Computational investigation on microsolvation of the osmolyte glycine betaine [GB (H2O)1-7]

The preferential interactions of glycine betaine (GB) with solvent components and the effect of solvent on its stability have been examined. In particular, the microsolvation of organic osmolyte and widely important osmoprotectant in nature as glycine betaine has been reported by using M06 method. A number of configurations (b_X (a-z)) of the clusters for one to seven water molecules (×?=?1-7) have been considered for the microsolvation. Structures of stable conformers are obtained and denoted as b1a, b2a, b3a, b4a, b5a, b6a and b7a. It is observed from the interaction energy difference (?E) that only seven water molecules can be accommodated in the first solvation shell to stabilize GB. It is also observed that the calculated relative energy using M06 is in close agreement with calculations at the MP2 level of theory.

A UB3LYP and UMP2 theoretical investigation on unusual cation–π interaction between the triplet state HB=BH ( {}^3\Sigma_g^{-} ) and H+, Li+, Na+, Be2+ or Mg2+

The nature of the unusual cation–π interactions between cations (H⁺, Li⁺, Na⁺, Be²⁺ and Mg²⁺) and the electron-deficient B=B bond of the triplet state HB=BH ( $ {}^3\Sigma_g^{-} $ ) was investigated using UMP2(full) and UB3LYP methods at 6–311++G(2df,2p) and aug-cc-pVTZ levels, accompanied by a comparison with 1:1 and 2:1 σ-binding complexes between BH and the cations. The binding energies follow the order HB=BH...H⁺ > HB=BH...Be²⁺ > HB=BH...Mg²⁺ ? HB=BH...Li⁺ > HB=BH...Na⁺ and HB=BH (¹Δ_g)...M⁺/M²⁺ > H₂C=CH₂...M⁺/M²⁺ > HC≡CH...M⁺/M²⁺ > HB=BH ( $ {}^3\Sigma_g^{-} $ )...M⁺/M²⁺. Furthermore, except for HB...H⁺, the σ-binding interaction energy of the 1:1 complex HB...M⁺/M²⁺ is stronger than the cation–π interaction energy of the C₂H₂...M⁺/M²⁺, C₂H₄...M⁺/M²⁺, B₂H₂ (¹Δ_g)...M⁺/M²⁺ or B₂H₂ ( $ {}^3\Sigma_g^{-} $ )...M⁺/M²⁺ complex, and, for the 2:1 σ-binding complexes, except for HBBe²⁺...BH, they are less stable than the cation–π complexes of B₂H₂ (¹Δ_g) or B₂H₂ ( $ {}^3\Sigma_g^{-} $ ). The atoms in molecules (AIM) theory was also applied to verify covalent interactions in the H⁺ complexes and confirm that HB=BH ( $ {}^3\Sigma_g^{-} $ ) can be a weaker π-electron donor than HB=BH (¹Δ_g), H₂C=CH₂ or HC≡CH in the cation–π interaction. Analyses of natural bond orbital (NBO) and electron density shifts revealed that the origin of the cation–π interaction is mainly that many of the lost densities from the π-orbital of B=B and CC multiple bonds are shifted toward the cations.

Density functional theoretical study on the preferential selectivity of macrocyclic dicyclohexano-18-crown-6 for Sr+2 ion over Th+4 ion during extraction from an aqueous phase to organic phases with different dielectric constants

The preferential selectivity of dicyclohexano-18-crown-6 (DCH18C6) for bivalent Sr⁺² ion over tetravalent Th⁺⁴ ion was investigated using generalized gradient approximated (GGA) BP86 and the hybrid B3LYP density functional, employing split valence plus polarization (SV(P)) and triple-zeta valence plus polarization (TZVP) basis sets in conjunction with the COSMO (conductor-like screening model) solvation approach. The calculated theoretical selectivity of DCH18C6 for Sr⁺² ion over Th⁺⁴ ion was found to be in accord with the selectivity for Sr⁺² ion over Th⁺⁴ ion observed when performing liquid–liquid extraction experiments in different organic solvents. While 1:1(M:L) stoichiometric complexation reactions can be used to predict the preferential selectivity of Sr²⁺ ion over Th⁴⁺ ion, the results obtained are not consistent with the experimental results observed upon increasing the dielectric constant of the solvent. The calculated theoretical gas-phase data for the free energy of complexation, ?G, fail to explain the selectivity for Sr⁺² ion over Th⁺⁴ ion. However, when 1:2 (M:L) stoichiometric complexation reactions (reported in previous X-ray crystallography studies) are considered, correct and consistent results for the selectivity for Sr⁺² ion over a wide range of dielectric constants are predicted. The distribution constant for Sr²⁺ and Th⁴⁺ ions was found to gradually increase with increasing dielectric constant of the organic solvent, and was found to be highest in nitrobenzene. The selectivity data calculated from ??G _ext are in excellent agreement with the results obtained from solvent extraction experiments.

Structure and spectral characteristics of diquat-cucurbituril complexes from density functional theory

Electronic structure, ¹H NMR and infrared spectra of diquat (6,7-dihydrodipyrido[1,2-b:1′,2′-e] pyrazine-5,8-diium or DQ²⁺) encapsulated by cucurbit[n]uril (n?=?7,8) hosts are obtained using the density functional theory. Theoretical calculations have shown that both CB[7] or CB[8] host possesses strong affinity toward DQ²⁺ compared to its reduced cation or neutral species. Calculated ¹H NMR spectra reveal that H_α protons on bi-pyridinium rings of DQ²⁺@CB[8] complex are de-shielded owing to C=O?H interactions. On the other hand aromatic (H_β and H_δ) of DQ²⁺ within the CB[8] cavity exhibit significant shielding. The complexation of CB[8] with DQ²⁺ splits the carbonyl stretching vibration (1788 cm^?1) into two distinct vibrations which correspond to 1765 cm^?1 arising from hydrogen bonded carbonyls and the 1792 cm^?1 band from non-interacting ones. Further, the CN stretching vibration in DQ²⁺ exhibits a frequency blue-shift of 6 cm^?1 on its encapsulation within the CB[8] cavity. The direction of frequency shift has been explained on the basis of natural bond orbital analyses.

Fine structure in the transition region: reaction force analyses of water-assisted proton transfers

We have analyzed the variation of the reaction force F(ξ) and the reaction force constant κ(ξ) along the intrinsic reaction coordinates ξ of the water-assisted proton transfer reactions of HX-N = Y (X,Y = O,S). The profile of the force constant of the vibration associated with the reactive mode, k _ξ (ξ), was also determined. We compare our results to the corresponding intramolecular proton transfers in the absence of a water molecule. The presence of water promotes the proton transfers, decreasing the energy barriers by about 12 – 15 kcal mol^-1. This is due in part to much smaller bond angle changes being needed than when water is absent. The κ(ξ) profiles along the intrinsic reaction coordinates for the water-assisted processes show striking and intriguing differences in the transition regions. For the HS-N = S and HO-N = S systems, two κ(ξ) minima are obtained, whereas for HO-N = O only one minimum is found. The k _ξ (ξ) show similar behavior in the transition regions. We propose that this fine structure reflects the degree of synchronicity of the two proton migrations in each case.

Relativistic theoretical studies on hydrogen bonds and the electronic structure of aqueous solvated bis(uranyl) complex: an insight into explicit and/or implicit solvent effects

To understand the chemical behavior of uranyl complexes in water, a bis-uranyl [(phen)(UO₂)(μ₂–F)(F)]₂ (A; phen?=?phenanthroline, μ₂?=?doubly bridged) and its hydrated form A?·?(H₂O)_n (n?=?2, 4 and 6) were examined using scalar relativistic density functional theory. The addition of water caused the phen ligands to deviate slightly from the U₂(μ₂–F)₂ plane, and red-shifts the U–F-terminal and U?=?O stretching vibrations. Four types of hydrogen bonds are present in the optimized hydrated A?·?(H₂O)_n complexes; their energies were calculated to fall within the range 4.37–6.77 kcal mol^-1, comparable to the typical values of 5.0 kcal mol^-1 reported for hydrogen bonds. An aqueous environment simulated by explicit and/or implicit models lowers and re-arranges the orbitals of the bis-uranyl complex.

Effect of metal ions (Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+ and Zn2+) and water coordination on the structure and properties of l-histidine and zwitterionic l-histidine

Interactions between metal ions and amino acids are common both in solution and in the gas phase. The effect of metal ions and water on the structure of l-histidine is examined. The effect of metal ions (Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, Ni²⁺, Cu²⁺ and Zn²⁺) and water on structures of His·M(H₂O)m, m = 0.1 complexes have been determined theoretically employing density functional theories using extended basis sets. Of the five stable complexes investigated the relative stability of the gas-phase complexes computed with DFT methods (with one exception of K⁺ systems) suggest metallic complexes of the neutral l-histidine to be the most stable species. The calculations of monohydrated systems show that even one water molecule has a profound effect on the relative stability of individual complexes. Proton dissociation enthalpies and Gibbs energies of l-histidine in the presence of the metal cations Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, Ni²⁺, Cu²⁺ and Zn²⁺ were also computed. Its gas-phase acidity considerably increases upon chelation. Of the Lewis acids investigated, the strongest affinity to l-histidine is exhibited by the Cu²⁺ cation. The computed Gibbs energies ΔG are negative, span a rather broad energy interval (from ?130 to ?1,300 kJ/mol), and upon hydration are appreciably lowered.     

Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis—a computational approach

Density functional theory (DFT) calculations at B3LYP/6-31 G (d,p) and B3LYP/6-311?+?G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pK _a value of the catalyst. Substituted-pyridine derivatives with high pK _a values were able to catalyze isomerization more efficiently than those with low pK _a values. The calculated relative rates for prodrugs 1–6 were: 1 (406.7), 2 (7.6?×?10⁶), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2?×?10³). This result indicates that isomerizations of prodrugs 1 and 3–5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 3–5 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis.