Vanessa Labet

Hydrolytic deamination of 5-methylcytosine in protic medium--a theoretical study.

The mechanism for the deamination reaction of 5-methylcytosine with H2O in protic medium was investigated using DFT calculations at the B3LYP/6-311G(d,p) level of theory. Two pathways were found. Pathway 5mA is a two-step mechanism where the N3-protonated 5-MeCyt undergoes a nucleophilic attack to carbon C4 by a water dimer before the elimination of an ammonium cation. Pathway 5mB is a three-step mechanism where neutral 5-MeCyt is directly attacked by a water dimer. The resulting intermediate is then protonated to allow the elimination of an ammonium cation. Both pathways lead to the formation of thymine in interaction with an ammonium cation and a water molecule. Pathway 5mA can explain the spontaneous deamination of 5-MeCyt in protic medium at acidic pH, whereas pathway 5mB is more representative of the deamination in protic medium at neutral pH. The nucleophilic addition of the water dimer is rate-determining in both pathways and is associated with an activation free energy in aqueous solution of 137.4 kJ/mol for pathway 5mA and 134.1 kJ/mol for pathway 5mB. This latter value is in agreement with the experimental observation that 5-MeCyt deaminates four- to fivefold faster than Cyt at neutral pH. Both electrostatic and electron-transfer contributions appear to have significant importance. In vacuum, the former one dominates when the substrate is positively charged and the latter one when it is neutral.

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.

Theoretical Study of Cytosine Deamination from the Perspective of the Reaction Force Analysis

A theoretical study of two different mechanisms for the spontaneous deamination of cytosine is presented. In the first mechanism, a tetrahedral intermediate results in a two-step mechanism whereas in the second one, it is the result of a concerted step. In this work a link is made between the two pathways through the study of the evolution along the reaction coordinates of chemical concepts such as chemical potential, hardness and electronic populations within the framework of the reaction force analysis. The reaction force profile suggests that the concerted mechanism is composed of two asynchronous events. The observation of the reaction force profile appears as an easy way to identify asynchronous concerted steps and as a privileged tool to study the more or less asynchronous character of chemical reactions.

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.

Deamination of the Radical Cation of the Base Moiety of 2'-Deoxycytidine : A Theoretical Study

Five pathways leading to the deamination of cytosine (to uracil) after formation of its deprotonated radical cation are investigated in the gas phase, at the UB3LYP/6-311G(d,p) level of theory, and in bulk aqueous solvent. The most favorable pathway involves hydrogen-atom transfer from a water molecule to the N3 nitrogen of the deprotonated radical cation, followed by addition of the resulting hydroxyl radical to the C4 carbon of the cytosine derivative. Following protonation of the amino group (N4), the C4--N4 bond is broken with elimination of the NH3+(. ) and formation of a protonated uracil. The rate-determining step of this mechanism is hydrogen-atom transfer from a water molecule to the cytosine derivative. The associated free energy barrier is 70.2 kJ mol(-1).

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.

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.

Comparison of the mechanism of deamination of 5,6-dihydro-5-methylcytosine with other cytosine derivatives

The mechanism of deamination of 5,6-dihydro-5-methylcytosine has been investigated theoretically and compared to those of other cytosine derivatives. The main goal is to understand the effect of C5-methylation and C5–C6 saturation upon the deamination rate. It is found that C5–C6 saturation tends to increase the local electrophilicity of the cytosine derivative on carbon C4. It is also concluded that C5-methylation displays an opposite effect on saturated versus unsaturated systems: on unsaturated systems, C5-methylation tends to increase the local electrophilicity on C4, while it reduces the local electrophilicity on C4 for saturated ones.