I. V. Rogachevskii

Ab initio conformation analysis of ouabain and ouabagenin molecules

Full conformation analysis of molecules of cardiotonic steroids ouabain and ouabagenin was performed. Full ab initio optimization of the geometric parameters of all the possible conformations of these molecules was made. The calculations were performed by the restricted Hartree Fock method in the 6–31G* basis set using GAMESS program. The effect of various factors on the steric and electronic structure of ouabain and ouabagenin was analyzed. The major factor affecting the geometric and electronic structure of ouabain and ouabagenin molecules is the conformation of ring A of the steroid core.

Possible molecular effect related to the reception of low-intensity IR radiation: Role of Src-kinase

The patch-clamp technique has been used to demonstrate that low-intensity IR irradiation affects the effective charge of the activation gating system of slow sodium channels in the nociceptive neuron membrane. IR photons are absorbed by ATP molecules bound to Na+,K+-ATPase at their hydrolysis site. Na+,K+-ATPase is a transducer of signal that is further delivered to slow sodium channels and cell genome. It is demonstrated that the irradiation does not modulate the response of a sensory neuron in the presence of PP2, an inhibitor of Src-kinase. The results show that Src-kinase is a series unit involved in the intracellular cascade processes triggered by low-intensity radiation of CO2 laser.

Quantum-chemical study on calcium(II) chelates with ouabagenin

Complete conformational analysis of 1: 1 calcium(II) chelates with ouabagenin was performed ab initio. Analysis of the effect of complex formation on the steric and electronic structures revealed that ouabagenin molecule is capable of coordinating Ca2+ ion in three different modes. The lack of rhamnose fragment in the ouabagenin molecule, in contrast to ouabain, sharply reduces its physiological activity related to its ability to bind at transducer Na+/K+-ATPase site.

Nonempirical conformational analysis of oubaine molecule chelate complexes with Ca2+ and possible mechanism of modulation of transductor function of Na+,K+-ATPhase

Complete conformational analysis of chelate complex of oubaine molecule with Ca2+ in 1:1 stoichiometry is carried out. Complete ab initio optimization of geometric parameters of all possible structures of the complexes is performed in the framework of restricted Hartree-Fock method with 6–31G* basis using GAMESS program. Influence of the complex formation on the steric structure and electronic structure of oubaine molecule is analyzed. Oubaine molecule is found capable of binding Ca2+ by two modes. Mechanism of binding of oubaine molecule with transductor site of Na+,K+-ATPhase is proposed: ligand-receptor interaction is assumed to be realized in account of formation of trial complex oubaine-Ca2+-Na+,K+-ATPhase, with main contribution to the interaction energy of ion-ion bonds formation between Ca2+ and nucleophilic functional groups in the composition of the mentioned binding site of Na+,K+-ATPhase.

Quantum-chemical study of the equilibrium geometry and electronic structure of certain γ-pyrone derivatives

Full ab initio optimization of molecular geometry has been carried out for certain γ-pyrone derivatives: comenic, meconic, chelidonic, and kojic acids and 5-methoxy-γ-pyrone-2-carboxylic acid in the forms of free acids, their anions, sodium and calcium salts, chelate complexes with Ca2+, and sodium and calcium salts of the chelate complexes. The calculations were carried out by the restricted Hartree-Fock method with the 6-31G* basis using the GAMESS program. The effect of salt and complex formation on the geometric and electronic structure of the molecules under consideration has been examined. To study the effect of solvation, full geometry optimization of comenic acid and its derivatives in media with the dielectric constants ɛ 10 and 78.3 has been was carried out in terms of the polarizable continuum model. The energy effects of salt and complex formation has been estimated. A possible mechanism of binding of the molecules under consideration with opioid receptors has been proposed on the basis of the calculation results.

The Defensin Receptor: A Possible Mechanism Responsible for Reduced Excitability of the Neuronal Sensory Membrane

Analysis of the antimicrobial properties of animal neutrophils revealed a family of lysosomotropic cationic low-molecular peptides, called defensins, in a granule-rich cytoplasmic fraction of these cells [1, 2]. By now, these peptides have been isolated from many mammalian species, and their primary structure has been characterized [1, 3]. A high content of arginine (from four to ten residues), which is a distinctive feature of defensins, largely determines their positive charge and, consequently, a relatively high dipole moment [4, 5]. This makes electrostatic interaction between defensins and acid bacterial phospholipids possible. In other words, electrostatic forces initiate defensin antibiotic effects. In addition, the high content of amino acids with hydrophobic side chains (isoleucine, proline, valine, phenylalanine, and alanine) characteristic of defensins is favorable for its dissolution in the lipid bilayer of cell membranes; moreover, defensins form membrane channels passing ions and small molecules [6, 7]. The role of defensins as membrane perforators probably determines their antibiotic effect [1, 3]. On the other hand, an organism’s own cells should be protected from the “perforating” effect of defensins, which should, therefore, be recognizable. This allows the existence of defensin receptors to be predicted. In this study, defensin NP-1 was found to bind to the membrane of a sensor neuron at a stoichiometric ratio 1 : 1. Interaction between the membrane receptor and defensin molecule is brought about via a single outwardly directed hydroxyl group within the carboxyl group of the defensin’s amino acid residue Glu 14 . The cultivated neurons of spinal ganglia isolated from Wistar rats were used in our experiments. The isolation of dorsal ganglia, their cultivation, and the detection of ionic currents by the patch-clamp method were described previously [8]. The following standard solutions were used (concentrations are given in mmol/l). The extracellular solution: NaCl, 65; CaCl 2 , 2; MgCl 2 , 2; Choline Cl, 70; HEPES–Na, 10; TTX, 0.0001; the pH was 7.4. The intracellular solution: CsF, 100; NaCl, 10; CsCl, 40; MgCl 2 , 2; HEPES–Na, 10; pH 7.2. The equilibrium geometry of a defensin molecule was reconstructed by the method of molecular mechanics HYPERCHEM.

Quantum-chemical study on the electronic structure and ligand-receptor binding mechanisms of some pyridin-4(1H)-one and pyran-4-one derivatives

Molecular structure optimization of a series of pyridin-4-one and pyran-4-one derivatives, namely 5-hydroxy-2-hydroxymethylpyridin-4(1H)-one, 5-hydroxy-1-methyl-4-oxo-1H-pyridine-2-carboxylic acid, and 5-hydroxy-2-hydroxymethylpyran-4-one (kojic acid) as free acids, the corresponding anions, calcium salts, calcium chelates, and calcium chelate calcium salts, was performed ab initio in terms of the restricted Hartree-Fock method with 6-31G* basis set using GAMESS program. The effects of salt and complex formation on the geometric and electronic structure of these molecules were analyzed. The solvation effects were examined by complete geometry optimization of all substrates in terms of the polarized continuum model (PCM) with dielectric constants ɛ of 10 and 78.3. The energies of formation of the salts and complexes were estimated. A set of geometric parameters responsible for the possibility of ligand-receptor binding with participation of pyran-4-ones and pyridin-4(1H)-ones and probable mechanism of binding of the latter to opioid receptors were proposed on the basis of the calculation data.

Possible Mechanism of Infrared Radiation Reception: The Role of the Temperature Factor

The role of the temperature factor in the mechanism of reception of the CO2 laser low-power infrared (IR) radiation (λ = 10.6 μm) by a sensory neuron membrane has been studied. Organotypic embryonic tissue culture has been used to measure and estimate the temperature of a sensory ganglia monolayer exposed to radiation at different energy densities. The effects of tissue exposure to low-power IR radiation have been investigated. It has been found that inhibition of tissue growth by radiation of low energy density (10–14–10–10 J/cm2) is replaced by tissue growth (10–7–10–4 J/cm2), and again followed by inhibition in the range of 0.1–6 J/cm2. A statistically significant specific reaction to nonthermal radiation has been detected at the radiation power density of 3 × 10–10 J/cm2, which is due to activation of the Na+,K+-ATPase transducer function. The mechanisms of interaction of IR radiation with embryonic nerve tissue have been considered. Low-power IR radiation with the wavelength of 10.6 μm has been demonstrated to specifically activate a novel signal transducer function of the sodium pump, which controls the reception of nonthermal IR radiation in the energy density range of 10–14 to 10–10 J/cm2.

Ab initio conformational analysis of marinobufagenin molecule and molecular targets of the action of cardiotonic steroids

Complete conformational analysis of marinobufagenin molecule was fulfilled by ab initio calculations. The comparison of results obtained with analogous calculations of ouabain and ouabagenin molecules made it possible to understand the effect of decrease in the effective charge on the voltage-gated slow sodium channels Nav1.8 experimentally detected by the local fixation of potential. A mechanism is suggested of the interaction between the mentioned cardiotonic steroids with the membrane of the sensor neuron.

Geometric structure of a molecule of epitalon tetrapeptide : A molecular-dynamics simulation

Variation of the geometric parameters of a molecule of Epitalon tetrapeptide (Ala-Glu-Asp-Gly) over a period of 1500 ps was simulated by the method of molecular dynamics using AMBER force field. The structure of the molecule is stabilized by two salt bridges formed by the N-terminal nitrogen atom and oxygen atoms of Asp and Glu side chains. The biological effect of Epitalon was attributed to formation of salt or hydrogen bonds involving one or several ionizable functional groups of the molecules.