Formation Mechanism of Inter-Crosslink in DNA by Nitrogen Oxides Pollutants through A Diazonium Intermediate.

Outdoor air pollution is a mixture of multiple atmospheric pollutants, among which nitrogen oxide (NOx) stands out due to its association with several diseases. NOx reactivity can conduct to DNA damage as severe as interstrand crosslinks (ICL) formation, that in turn is able to block DNA replication and transcription. Experimental studies have suggested that the ICL formation due to NOx is realized through a diazonium intermediate (DI). In this work, we have modeled the DI structure, including a DNA double-strand composed of two base pairs GC/CG, being diazotized as one of the guanine nucleotides. The structural stability of DNA with DI lesion was essayed through 500 ns molecular dynamics simulations. It was found that the DNA structure of the oligonucleotide is stable when the DI is present since the loss of a Guanine-Cytosine hydrogen bond is replaced by the presence of two cation-π interactions. Additionally, we have studied the mechanism of formation of a crosslink between the two guanine nucleobases from the modeled DI by carrying out DFT calculations at the M06-L/DNP+ level of theory. Our results show that the mechanism is thermodynamically favored by a strong stabilization of the ICL product, and the process is kinetically viable since its limiting stage is accessible.

Theoretical study of the gas-phase thermolysis reaction of 3,6-dimethyl-1,2,4,5-tetroxane. Methyl and axial-equatorial substitution effects.

Organic peroxides are interesting compounds with a broad range of properties from antimalarial and antimicrobial activities to explosive character. In this work the gas-phase thermolysis reaction mechanism of the 3,6-dimethyl-1,2,4,5-tetroxane (DMT) is studied by DFT calculations, considering axial-axial, axial-equatorial, and equatorial-equatorial position isomers. The critical points of the singlet (S) and triplet (T) potential energy surfaces (PES) are calculated. Three mechanisms are considered: i) S-concerted, ii) S-stepwise, and iii) T-stepwise. The first intermediate of the reaction through S-stepwise-PES is a diradical open structure, o, yielding, as products, two molecules of acetaldehyde and one of O2 in the S state. The S-stepwise-mechanism gives exothermic reaction energies (Er) in the three position isomers. The S-concerted mechanism yields very high activation energies (Ea) in comparison with those of the S-stepwise mechanism. In the T-stepwise mechanism, a triplet open structure (T-o) is first considered, yielding an Er 12 kcal mol-1 more exothermic than that of the S-mechanisms. The S-o and T-o are similar in structure and energies; therefore, a crossing from the S- to T-PES is produced at the o intermediate as a consequence of a spin-orbit coupling. The highest Ea is the first step after o intermediate, and thus it is considered the rate limiting step. Therefore, the Er at the T-PES is more in agreement with the Er of the exothermic experimental diperoxide products. Ea, Er, and O···O distances are studied as a function of the number of methyl groups and the position isomerization.

Correction: Towards the rationalization of catalytic activity values by means of local hyper-softness on the catalytic site: a criticism about the use of net electric charges.

Correction for 'Towards the rationalization of catalytic activity values by means of local hyper-softness on the catalytic site: a criticism about the use of net electric charges' by Jorge Ignacio Martínez-Araya et al., Phys. Chem. Chem. Phys., 2015, DOI: 10.1039/c5cp03822g.

Towards the rationalization of catalytic activity values by means of local hyper-softness on the catalytic site: a criticism about the use of net electric charges.

By means of the Spin-Polarized Conceptual Density Functional Theory (SP-CDFT), three 2,6-bis(imino)pyridine catalysts based on iron(II), used for polymerization of ethylene, were studied. The catalysts differed by the substituent group, bearing either -H, -NO2 or -OCH3. To date, catalytic activity, a purely experimental parameter measuring the mass of polyethylene produced per millimole of iron per time and pressure unit at a fixed temperature, has not been explained in terms of local hyper-softness. The latter is a purely theoretical parameter designed for quantifying electronic effects; it is measured using the metal atom responsible for the coordination process with the monomer (ethylene). Because steric effects are not relevant in these kinds of catalysts and only electronic effects drive the catalytic process, an interesting link is found between catalytic activity and the local hyper-softness condensed on the iron atom by means of four functionals (B3LYP, BP86, B97D, and VSXC). This work demonstrates that the use of local hyper-softness, predicted by the SP-CDFT, is a suitable parameter for explaining order relationships among catalytic activity values, thus quantifying the electronic influence of the substituent group inducing this difference; the use of only net electric charges does not lead to clear conclusions. This finding can aid in estimating catalytic activities leading to a more rational design of new catalysts via computational chemistry.

Solar UV radiation-induced DNA Bipyrimidine photoproducts: formation and mechanistic insights.

This review chapter presents a critical survey of the main available information on the UVB and UVA bipyrimidine photoproducts which constitute the predominant recipient classes of photo-induced DNA damage. Evidence is provided that UVB irradiation of isolated DNA in aqueous solutions and in cells gives rise to the predominant generation of cis-syn cyclobutane pyrimidine dimers (CPDs) and, to a lesser extent, of pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), the importance of which is strongly primary sequence dependent. A notable change in the photoproduct distribution is observed when DNA either in the dry or in desiccated microorganisms is exposed to UVC or UVB photons with an overwhelming formation of 5-(α-thymidyl)-5,6-dihydrothymidine, also called spore photoproduct (dSP), at the expense of CPDs and 6-4PPs. UVA irradiation of isolated and cellular DNA gives rise predominantly to bipyrimidine photoproducts with the overwhelming formation of thymine-containing cyclobutane pyrimidine dimers at the exclusion of 6-4PPs. UVA photons have been shown to modulate the distribution of UVB dimeric pyrimidine photoproducts by triggering isomerization of the 6-4PPs into related Dewar valence isomers. Mechanistic aspects of the formation of bipyrimidine photoproducts are discussed in the light of recent photophysical and theoretical studies.

Deamination features of 5-hydroxymethylcytosine, a radical and enzymatic DNA oxidation product.

The 5-methylcytosine derivative 5-hydroxymethylcytosine (5hmCyt), which is generated via enzymatic oxidation, is sometimes referred to as the sixth nucleobase due to its widespread presence in the DNA of brain and embryonic stem cells. In this study, we used density functional based methods and reactivity indices from conceptual DFT to explore the mechanism and key features of the hydrolytic deamination of 5hmCyt. The data obtained are used to compare and contrast this deamination reaction with those of other cytosine derivatives. The deamination process for 5hmCyt is similar to the corresponding processes for other unsaturated derivatives in that the amino form is the reactive one and water addition is the rate-limiting step. However, several differences due to the rotameric asymmetry of the current system are also noted.

Theoretical study of the gas-phase thermolysis of 3-methyl-1,2,4,5-tetroxane.

Cyclic organic peroxides are a broad and highly sought-after class of peroxide compounds that present high reactivity and even explosive character. The unusually high reactivity of these peroxides can generally be attributed to the rupture of O-O bonds. Cyclic diperoxides are a very interesting series of substituted compounds in which tetroxane is the most prominent member. Gas-phase thermolysis of the simplest substituted member of the series [3-methyl-1,2,4,5-tetroxane or methylformaldehyde diperoxide (MFDP)] has been observed to yield one acetaldehyde, one formaldehyde, and one oxygen molecule as reaction products. DFT at the 6-311 + G** level of theory using the BHANDHLYP correlation-exchange functional was applied via the Gaussian09 program to calculate the critical points of the potential energy surface (PES) of this reaction. Equatorial and axial isomers were studied. The singlet state PES of MFDP was calculated, and an open diradical structure was found to be the first intermediate in a stepwise reaction. Two PESs were subsequently obtained: singlet state (S) and triplet state (T) PESs. After that, two alternative stepwise reactions were found to be possible: 1) one in which either an acetaldehyde, or 2) formaldehyde molecule is initially formed. For second one, exothermic reactions were observed for both the S and T PESs. The reaction products include a oxygen molecule in either S or T state, with the T reaction being the most exothermic. When calculations were performed at the CASSCF(10,10)/6-311 + G** level, spin-orbit coupling permitted S to T crossing at the open diradical intermediate stage, a non-adiabatic reaction was observed, and lower activation energies and higher exothermicity were generally seen for the T PES than for the S PES. These results were compared with the corresponding results for tetroxane. The spin-orbit coupling of MFDP and tetroxane yielded identical values, so it appears that the methyl substituent does not have any effect on this coupling.

UV-induced formation of the thymine-thymine pyrimidine (6-4) pyrimidone photoproduct--a DFT study of the oxetane intermediate ring opening.

The mechanism by which the hypothetical oxetane/azetidine intermediate formed during the photochemical process leading to pyrimidine (6-4) pyrimidone photoproducts when DNA is submitted to UV radiation opens is investigated computationally by DFT using a 5'-TT-3' dinucleoside monophosphate as a structural model. First, the feasibility of an intramolecular mechanism involving one proton transfer inducing opening of the oxetane ring is examined. It results in a very high Gibbs energy of activation (+166 kJ mol(-1)) and quite a low Gibbs energy of reaction (-35 kJ mol(-1)). The protonation state of the phosphate group is shown to have little effect while the bulk effect of an aqueous environment modeled by the Polarizable Continuum Model method lowers slightly the activation barrier (by about 10-20 kJ mol(-1)), not enough to explain the fact that the oxetane intermediate is not observed experimentally. Then the catalytic effect of water molecules on the reaction pathway is studied by including either 1 or 2 assisting water molecules in the chemical system. The resulting activation barrier is considerably lowered and in the most favorable situation - a phosphate group deprotonated and 2 assisting water molecules - the Gibbs energy activation is as low as +44 kJ mol(-1) and the Gibbs energy of reaction is quite favorable: -79 kJ mol(-1), suggesting that in biological systems the oxetane ring opening process proceeds with explicit intervention of water molecules from the environment.

Is hyper-hardness more chemically relevant than expected?

In this work, the third derivative of the energy with respect to the number of electrons, the so-called hyper-hardness, is investigated to assess whether this quantity has a chemical meaning. To achieve this goal a new working expression for hyper-hardness is developed and analyzed. It transpired from this analysis that hyper-hardness, just like hardness, can measure the reactivity or the stability of electron systems. Interestingly, positive values of hyper-hardness point to quite stable species such as noble gases and molecules. On the other hand, radicals almost always display large negative values of hyper-hardness.

A physicochemical examination of the free radical scavenging activity of Trolox: mechanism, kinetics and influence of the environment.

The free radical scavenging activity of Trolox was studied for aqueous and lipid environments using the Density Functional Theory. Several reaction mechanisms and free radicals of different chemical nature have been included in this study, as well as the influence of the pH. Trolox was found to be a powerful ˙OH and alkoxy scavenger, regardless of the conditions under which the reaction takes place. It was also found to be very efficient as a peroxy radical scavenger in aqueous solution, while its protective effects against this particular kind of free radicals are significantly reduced in lipid solution. Four reaction mechanisms were found to significantly contribute to the ˙OH scavenging activity of Trolox in aqueous solution: hydrogen transfer (HT), radical adduct formation (RAF), single electron transfer (SET), and sequential proton loss electron transfer (SPLET), while in lipid media two of them are relevant: HT and RAF. The ˙OCH3, ˙OOH, and ˙OOCHCH2 scavenging processes are predicted to take place almost exclusively by HT from the phenolic OH group in lipid media, and in aqueous solution at pH < 11, while at higher pH values the SPLET mechanism is proposed as the main one. This is also the case for other non-halogenated alkyl or alkenyl peroxy (and alkoxy) radicals. The agreement with the available experimental data supports the reliability of the presented calculations.

A relation between different scales of electrophilicity: are the scales consistent along a chemical reaction?

In this paper, a relationship is established between three electrophilicity scales, namely, the electrophilicity index defined by Parr, Liu, and von Szentpaly; the electron affinity; and the energy of the lowest unoccupied molecular orbital (LUMO). Profiles of electrophilicity index and LUMO energies for different kinds of chemical reactions are compared to verify if they remain consistent during a whole chemical process. It appears that the electrophilicity index and the LUMO energies are linearly correlated in almost all the cases. Besides electrophilicity scales, profiles provide valuable information about the charge-transfer stage of a chemical process.

1,2-Dihydrotriazinyl-N-oxy free radicals.

Triazinyl-N-oxy free radicals, 2-methyl-2,4,6-triphenyl-1,2-dihydro-1,3,5-triazinyl-1-oxy (6a), 2,2,4,6-tetraphenyl-1,2-dihydro-1,3,5-triazinyl-1-oxy (6b), 2,2-dimethyl-4,6-diphenyl-1,2-dihydro-1,3,5-triazinyl-1-oxy (13), and 2,6-dimethyl-2,4-diphenyl-1,2-dihydro-1,3,5-triazinyl-1-oxy (14), in which the unpaired electron is delocalized over three nitrogen atoms, have been prepared and characterized. A method has been devised for introducing an N-oxide function into the triazinyl core. Then, by using a Grignard reagent, substitution α to the N-oxide group was achieved and the resulting 1,2-dihydrotriazine-N-oxide oxidized into the corresponding nitroxide. Solution EPR spectra exhibit hyperfine splitting that confirms spin delocalization over the three nitrogen atoms of the triazinyl ring. They also show that spin delocalization diminishes with increasing distance for the coupling and is largest for nitrogen N1 and weakest for N5. Free radicals 6a and 13 are stable in the solid state and have been characterized by X-ray diffraction, but they tend to gradually degrade in solution. In the solid state, these two free radicals are arranged into antiferromagnetically exchange-coupled pairs, J=-5.2(6) for 6a and -3.7(4) cm(-1) for 13 (H=-2JS(1)S(2)).

Use of the dual potential to rationalize the occurrence of some DNA lesions (pyrimidic dimers).

Exploiting the locality of the chemical potential of an excited state when it is evaluated using the ground state Density Functional Theory (DFT), a new local descriptor for excited states has been proposed (J. Chem. Theory Comput.2009, 5, 2274). This index is based on the assumption that the relaxation of the electronic density toward that of the ground state drives the chemical reactivity of excited states. The sign of the descriptor characterizes the electrophilic or nucleophilic behavior of atomic regions. Through an exact excited state DFT formalism provided by Gross, Oliveira, and Kohn, a mathematical argument is given for this descriptor only for the first excited state. It is afterward used to rationalize the occurrence and the regioselectivity of some DNA lesions based on the [2 + 2] cycloaddition between two adjacent bases.

Application of the electron density force to chemical reactivity.

In this paper the concept of force experienced by the electron density is applied to chemical reactivity. The force is based upon the gradient of a local chemical potential. Closely related concepts such as force field lines and local electron flux are defined to provide insight in chemical reactivity. The time evolution of a molecular site density is also proposed. From the divergence of the force, the nucleophilic and electrophilic behaviour of atomic sites are characterized. Finally, the relations between the force and local conceptual DFT descriptors are also given.

Inclusion of a nitronyl nitroxyl radical and its hydrochloride in cucurbit[8]uril.

The recognition properties of cucurbit[8]uril (CB8) toward nitronyl nitroxide 2-(2-benzimidazolyl)-4,4,5,5-tetramethylimidazolidinyl-3-oxide-1-oxy (1) and its hydrochloride have been investigated. 1·HCl led to 1:1 inclusion complex [1·HCl@CB8], which was characterized both in solution and by single-crystal X-ray diffraction. In this compound only the tetramethylimidazolidinyl fragment is included in the host. The magnetic behavior of the complex corresponds to a Curie law with a large separation of the spin carriers in the solid. In contrast, an insoluble species exhibiting ferromagnetic behavior is formed when pure 1 reacts with acid-free CB8. The formula [(1)(2)@(CB8)(3)], in which two radical guests are arranged in such a way that the phenyl groups of the benzimidazolyl substituents are both stacked into one CB8 and the tetramethyl fragments are each capped by a terminal macrocycle, is proposed, in agreement with microanalysis, spectrophotometric, EPR, and magnetic measurements. According to McConnell's rules, the alternating spin densities within the stacked aromatic fragments result in a ferromagnetic interaction (J=+2.3 cm(-1), H=-2JS(1)S(2)) and a triplet ground spin state for the inclusion complex.

Is an elementary reaction step really elementary? Theoretical decomposition of asynchronous concerted mechanisms.

In this paper the primitive process concept is used to reproduce and explain the potential energy profile of an asynchronous concerted mechanism. The number of primitive processes constituting such a mechanism can be deduced from the study of the influence of the number of electrons on the potential energy profile of the elementary step. The study of a particular example indicates that the position of the transition states of the primitive processes constituting an asynchronous concerted mechanism seems not to be affected by the number of electrons in the system. This implies that the maximum hardness and minimum electrophilicity principles are valid for primitive processes but not for asynchronous concerted mechanisms. It appears that a potential energy profile with a shoulder before the transition state, and a reaction force profile with more than two extrema together with a hardness profile presenting a minimum shifted with respect to the transition state are thus indicators of the presence of an asynchronous concerted mechanism.

Hydrolytic deamination of 5,6-dihydrocytosine in a protic medium: a theoretical study.

The mechanism for the deamination reaction of 5,6-dihydrocytosine with H(2)O in a protic medium was investigated by DFT calculations at the B3LYP/6-311G(d,p) level of theory as a model reaction for the deamination reaction of 5,6-saturated cytosine derivatives. Two pathways were found. Pathway dhA, which can explain the deamination in a protic medium at acidic pH, and pathway dhBt, more representative of the reaction in a protic medium at neutral pH. Pathway dhA is a two-step mechanism initiated by the nucleophilic addition of a water molecule to carbon C4 of N3-protonated 5,6-dihydrocytosine with the assistance of a second water molecule, followed by elimination of an ammonium cation to form 5,6-dihydrouracil. The nucleophilic addition is rate-determining with an activation free energy of 116.0 kJ/mol in aqueous solution. Pathway dhBt is a four-step mechanism which starts with the water-assisted tautomerization of 5,6-dihydrocytosine to form the imino tautomer. This intermediate undergoes nucleophilic addition of water to carbon C4, which after protonation eliminates an ammonium cation, as in pathway dhA. The nucleophilic addition is again rate-determining, with an activation free energy of 113.3 kJ/mol in aqueous solution. The latter value is about 25 kJ/mol lower than its counterpart for cytosine, in agreement with the experimental observation that 5,6-saturated cytosine derivatives exhibit a much shorter lifetime in aqueous solution than their unsaturated counterparts. The evaluation of reactivity indices derived from conceptual DFT leads to the conclusion that this lower activation free energy can be attributed to a larger local electrophilic power of carbon C4 in 5,6-saturated derivatives.

5',8-Cyclo-2'-deoxyadenosine (cdA) formation by gamma-radiation. Theoretical quantum mechanics study.

Reactions of reactive oxygen species and more specifically - of hydroxyl radical ((*)OH) - with nucleosides may lead to the generation of radicals in the base and 2-deoxyribose moieties. In the present study emphasis was put on the possible reaction modes of 2'-deoxyadenosine (dA) radicals, leading to the formation of related 5',8-cyclonucleosides. It appears that the prerequisite for the formation of 5',8-cyclo-2'-deoxyadenosine (cdA) is the adoption of O4'-exo conformation by 2-deoxyribose; however, this is the least energetically favored conformer among the different puckered forms adopted by the furanose ring. The O4'-exo conformation was found to be present in each of the discussed mechanisms.

Minimum electrophilicity principle: an analysis based upon the variation of both chemical potential and absolute hardness.

In this work, the minimum electrophilicity principle (MEP), assessed by either the electrophilicity power or the DeltaNmax, is mathematically analysed through the variation of both chemical potential and chemical hardness. It appears that the decrease of the electrophilicity power and the decrease of the DeltaNmax are ruled by similar expressions in which both the chemical potential and the absolute hardness should increase. A reduced expression at constant chemical potential shows that the MEP and the maximum hardness principle are equivalent. However it pops up from the monitoring of chemical processes such as bond formation and redox reactions that the variation of the chemical potential is the most important term.

Mechanism of nitric oxide induced deamination of cytosine.

A five-step mechanism is proposed for the NO -induced deamination of cytosine. It has been investigated using DFT calculations, including both explicit water molecules and a bulk solvent model to mimic an aqueous environment. According to this mechanism, cytosine first undergoes tautomerization with the assistance of a water molecule from the bulk. A NO(+) cation produced by the autooxidation of NO is subsequently added to the exocyclic imino group of the cytosine imine tautomer. The resulting adduct is able to undergo a tautomerization step with the participation of a water molecule to produce a cytosine in which a -N(2)OH group is attached to carbon C4. Protonation of the oxygen of the latter gives a water molecule which dissociates instantaneously, leading to a pyrimidinic diazonium cation. This constitutes the rate-determining step of the mechanism with an activation free energy of 92.6 kJ mol(-1). The last step, which is highly exergonic, represents the driving force of the reaction. It is the substitution of the -N(2)(+) terminal group by a water molecule which simultaneously allows the transfer of one of the two hydrogens to the bulk. Thus, the two products of the reaction consist of a nitrogen molecule and the enol tautomer of uracil in equilibrium with the keto form.