Leonid Gorb

A direct-dynamics study of proton transfer through water bridges in guanine and 7-azaindole

To evaluate the efficiency of bridges of water molecules as proton conduits, multidimensional ab initio proton transfer rate constants are reported for complexes of guanine and 7-azaindole with one and two water molecules. These water molecules form hydrogen-bonded bridges between functional groups involved in tautomerization via proton transfer and catalyze this transfer. Structures and energies of the relevant stationary configurations are optimized at the second-order Moller–Plesset level and vibrational force fields are evaluated at the Hartree–Fock level. The proton transfer rate constants, calculated with the instanton method, show the effect of the structure and strength of the hydrogen bonds, reflected in couplings between the tunneling mode and the other vibrations of the complexes. The results indicate that strongly hydrogen-bonded, strain-free water bridges can serve as very efficient proton conduits.

Structure-toxicity relationships of nitroaromatic compounds

SummaryThe toxicity data of 28 nitroaromatic compounds (nitrobenzenes and, for comparison, benzene and toluene) related to a 50% lethal dose concentration for rats (LD50) were used to develop quantitative structure-activity relationships (QSARs).A genetic algorithm and multiple regression analysis were applied to select the descriptors and to generate the correlation models. The obtained equations consist of one to three descriptors. A number of molecular descriptors was obtained from HF/6-31G(d) and DFT (B3LYP/6-311+G(d, p)) level calculations. The calculated molecular geometry and electronic properties were evaluated by comparison with the available experimental data (where applicable). All parameters obtained at the B3LYP/6-311+G(d, p) level and the topological descriptors derived from this geometry were found to be reliable, except for dipole moment, due to the large uncertainty of its estimation.Satisfactory relationships were observed for the one-parameter structure-toxicity models between topological (X5Av, Ms) and quantum-chemical (ELUMO) descriptors. For better predictability two- and three-parameter QSAR analyses were performed. These analyses resulted in much better equations with correlation coefficient values r = 0.872−0.924. These models have been obtained with a set of topological, fragment and quantum-chemical descriptors (Ms, PCR, PCD, BELe1, C-026 and ELUMO).The toxicity of nitroaromatic compounds appears to be governed by a number of factors, such as the number of nitrogroups, the electrotopological state, the presence of certain fragments and the electrophilicity/reactivity parameter (ELUMO). Nitrobenzenes exhibited electrophilic reactivity (as was shown by correlation of the toxicity with the energy of the lowest unoccupied orbital, ELUMO).The toxicity LD50 parameter for rats has been utilized for the first time for QSAR analysis of nitrobenzenes. The predictive ability of the models is determined by a cross-validation “leave-one-out” method.

Ab Initio Kinetic Simulation of Gas-Phase Experiments: Tautomerization of Cytosine and Guanine

A novel kinetic approach based on ab initio calculated rate constants has been developed and implemented in the kTSim program. The proposed approach allows prediction of the distribution of reactant and product concentrations over time, based exclusively on computationally obtained rate constants. The newly developed methodology was used to simulate the process of evaporation and tautomerization of guanine and cytosine under thermal (T = 490 K, cytosine; T = 620 K, guanine) and laser (T = 1000 K, 24 ns laser pulse) desorption conditions. Both monomolecular and bimolecular mechanisms of the tautomerization were considered simultaneously. The rates of the reactions were estimated using the values of Gibbs free energies calculated at the MPWB1K/aug-cc-pVDZ level and specified in a kTSim input. We expect that the proposed approach can also be used for accurate kinetic simulation of a wide range of processes.

Structural nonrigidity of nucleic acid bases. Post–Hartree–Fock ab initio study

Pyrimidine ring deformation modes in uracil, thymine, cytosine, isocytosine, guanine, and adenine were analyzed using normal vibrations calculated at the MP2/6-31G(d,p) levels of theory. We have introduced the theoretical approach based on the combined analysis of the shape of the relaxed potential surface, normal out-of-plane frequencies, and the amplitudes of the corresponding vibrations. We have shown that the absolute value of the frequency is not the unique characteristic to determine the lowest modes of the molecular deformation. We have revealed the applications involved in the analysis of the amplitudes to locate the internal coordinates (torsional angels), which correspond to the set of lowest energy deformations. It was demonstrated that the pyrimidine ring possesses high structural nonrigidity. Two very soft modes of ring deformation were found for every molecule except adenine. An estimation of population of excited vibrational levels for the lowest out-of-plane ring vibrations reveals that in every moment of time about 50% of all considered molecules possess a nonplanar configuration in the pyrimidine ring with a relevant torsion angle up to 25°

Novel view on the mechanism of water-assisted proton transfer in the DNA bases: bulk water hydration

In the present work, the conventional static ab initio picture of a water-assisted mechanism of the tautomerization of Nucleic Acid Bases (NABs) in an aqueous environment is enhanced by the classical and Car-Parrinello molecular dynamics simulations. The inclusion of the dynamical contribution is vital because the formation and longevity of the NAB-water bridge complexes represent decisive factors for further tautomerization. The results of both molecular dynamic techniques indicate that the longest time when such complexes exist is significantly shorter than the time required for proton transfer suggested by the static ab initio level of theory. New rate constants of tautomerization corrected for the dynamic effect of environment are proposed based on the first principles molecular dynamics data. Those values are used for the evaluation of a water-assisted mechanism that is feasible in such biological systems as E. coli cell.

A theoretical investigation of tautomeric equilibria and proton transfer in isolated and monohydrated cytosine and isocytosine molecules

Abstract The results of an ab initio post Hartree–Fock (HF) comparable study of the relative stabilities and mechanisms of intramolecular proton transfer in isolated and monohydrated cytosine and isocytosine molecules are reported. The geometries of local minima and transition states were optimized without symmetry restrictions by the gradient procedure at the HF and MP2 levels of theory and were verified by energy second derivative calculations. The standard 6-31G(d) basis set was used. The single point calculations have been performed at the MP4(SDQ)/6-31G(d,p)//MP2/6-31G(d) and MP2/6-311++G(d,p)//MP2/6-31G(d) approximations. The post HF ab initio theory predicts different distributions of the tautomers for cytosine and isocytosine both in the gas phase and in polar media (Onsagers self-consistent reaction field model). The interactions with one water molecule change the order of relative stability of cytosine and isocytosine tautomers to those corresponding to the experimentally measured relative stabilities in polar solutions. Ab initio calculations predict the heights of the proton transfer barriers for monohydrated nucleic bases to be approximately three times lower compared with non-water-assisted processes.

Conformational flexibility of pyrimidine ring in adenine and related compounds

Abstract The structural non-rigidity of aromatic pyrimidine rings in adenine and selected related compounds has been investigated by quantum chemical non-empirical methods of calculation at the MP2 and DFT levels of theory. The results of the calculations demonstrate that the pyrimidine ring possesses a notable degree of conformational flexibility despite its aromatic character. The transition of the heterocycle from a planar equilibrium geometry to a non-planar structure with an endocyclic torsion angle of ±20° results in an energy increase of less than 2.8 kcal/mol. An analysis of the population of ground and excited vibrational levels for the lowest out-of-plane vibration of the ring indicates that in adenine 45% of the molecules have a non-planar pyrimidine ring with relevant torsion angle up to ±17° at any moment of time.

Ab initio molecular dynamics study on the initial chemical events in nitramines: thermal decomposition of CL-20.

CL-20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane or HNIW) is a high-energy nitramine explosive. To improve atomistic understanding of the thermal decomposition of CL-20 gas and solid phases, we performed a series of ab initio molecular dynamics simulations. We found that during unimolecular decomposition, unlike other nitramines (e.g., RDX, HMX), CL-20 has only one distinct initial reaction channelhomolysis of the N-NO2 bond. We did not observe any HONO elimination reaction during unimolecular decomposition, whereas the ring-breaking reaction was followed by NO 2 fission. Therefore, in spite of limited sampling, that provides a mostly qualitative picture, we proposed here a scheme of unimolecular decomposition of CL-20. The averaged product population over all trajectories was estimated at four HCN, two to four NO2, two to four NO, one CO, and one OH molecule per one CL-20 molecule. Our simulations provide a detailed description of the chemical processes in the initial stages of thermal decomposition of condensed CL-20, allowing elucidation of key features of such processes as composition of primary reaction products, reaction timing, and Arrhenius behavior of the system. The primary reactions leading to NO2, NO, N 2O, and N2 occur at very early stages. We also estimated potential activation barriers for the formation of NO2, which essentially determines overall decomposition kinetics and effective rate constants for NO2 and N2. The calculated solid-phase decomposition pathways correlate with available condensed-phase experimental data.

Conformational analysis of canonical 2-deoxyribonucleotides. 1. Pyrimidine nucleotides.

Abstract The molecular structure and relative stability of north and south conformers of 2′-deoxyribonucleotides containing pyrimidine nucleic acid bases (2′-deoxythymidilic (pdT), 2′- deoxycytidilic (pdC) acids and their mono- and dianions) have been obtained and analyzed at the DFT/B3LYP level using the standard 6–31G(d) basis set. We have revealed that, when the nucleobase moiety is incorporated into the nucleotides, it maintains a nonplanar and nonrigid conformation due to out-of-plane deformation of the amino group and pyrimidine ring. It has been demonstrated that an increase of negative charge of the phosphate group results in increase of amino group pyramidalization, discrimination between conformers with syn and anti orientation of base with respect to sugar, strengthening of intramolecular C-H…O hydrogen bonds leading to deformation and fixation of geometry of nucleotides, and weakening of phosphodiester bond. These results allow to make suggestions about sources of twist and buckle deformations of base pairs, mechanisms of repaire of DNA via change of base orientation, and conditions for breakage of the P-O bonds during hydrolysis.

The interaction of nitrobenzene with the hydrate basal surface of montmorillonite: an ab initio study

The results of an ab initio Hartree–Fock study of the cluster molecular model mimicking the ditrigonal cavity of montmorillonite are reported. Full optimization of the geometry has been applied for the Si6Al6O30H18 cluster using the HF/6-31G(d) basis set. In order to obtain a model of the isomorphic substitution in the alumino oxygen layer of clay minerals, a magnesium atom has replaced one of the aluminium atoms of the alumino–oxygen layer in the cluster. To compensate for the negative charge which inevitably appears in this type of substitution, the Na+ exchangeable cation has been placed in the area with the most negative electrostatic potential in the basal plane of the cluster model. Finally, we have calculated the geometry and interaction energy for the adsorption complex which is formed by the interaction of nitrobenzene (the simplest nitroaromatic compound, having the chemical formula C6H5NO2) with the hydrated surface of clay minerals. The predicted BSSE corrected energy of the interaction is of the same order (11.8 kcal mol−1 at the B3LYP/6-31G(d)//HF/6-31G(d) level) as has been estimated for the adsorption of nitro-compounds interacting with full molecular contacts. We have concluded that this type of adsorption of nitro-compounds should be at least as effective as the adsorbtion which includes the donor–acceptor type of interactions with a nonhydrated silicon–oxygen surface.