RESUMO
At the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory it was established for the first time, that the Löwdin's G*.C* DNA base pair formed by the mutagenic tautomers can acquire, as the A-T Watson-Crick DNA base pair, four biologically important configurations, namely: Watson-Crick, reverse Watson-Crick, Hoogsteen and reverse Hoogsteen. This fact demonstrates rather unexpected role of the tautomerisation of the one of the Watson-Crick DNA base pairs, in particular, via double proton transfer: exactly the G.C-->G*.C* tautomerisation allows to overcome steric hindrances for the implementation of the above mentioned configurations. Geometric, electron-topological and energetic properties of the H-bonds that stabilise the studied pairs, as well as the energetic characteristics of the latters are presented.
Assuntos
Adenina/química , Citosina/química , DNA/química , Guanina/química , Mutação , Prótons , Timina/química , Pareamento de Bases , Ligação de Hidrogênio , Modelos Moleculares , Conformação de Ácido Nucleico , Estereoisomerismo , TermodinâmicaRESUMO
Using the methods of non-empirical quantum chemistry at the MP2/6-311++G(2df,pd)// B3LYP/6-311++G(d,p) level of theory it was established for the first time, that Hoogsteen, reverse Hoogsteen, Watson-Crick and reverse Watson-Crick configurations of the A.T and G.C DNA base pairs are isoelectronic and isomorphic structures with similar dynamic properties. Based on these results, non-ionisation mechanism of the Hoogsteen <"breathing" of the G*.C* DNA base pair, namely transformation of the tautomerised (Lowdin's) G-C base pair with Watson-Crick geometry into the Hoogsteen electroneutral G*.C* H base pair stabilized by the three O6H...N4, N3H...N7 and C8H...02 H-bonds, was postulated. It is suggested that such scenario activates only in those cases, when DNA is not located in aqueous solution, but works together with proteins and cytosine protonation at the N3 atom is precluded.
Assuntos
Adenina/química , Citosina/química , DNA/química , Guanina/química , Mutação , Prótons , Timina/química , Pareamento de Bases , Ligação de Hidrogênio , Modelos Moleculares , Conformação de Ácido Nucleico , Teoria Quântica , Estereoisomerismo , TermodinâmicaRESUMO
Using the simplest molecular models at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of the theory it has been shown for the first time that in addition to traditional incorporational errors caused by facilitated (compared with the canonical DNA bases cytosine (Cyt)) tautomerization of 6-(2-deoxy-beta-D-ribofuranosyl)-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-7-one (DCyt), this mutagen causes the replication errors, increasing one million times the population of mispair Gua.DCyt* (asterisk marked mutagenic tautomer) as compared with mispair Gua.Cyt*. It is also proved that DCyt in addition to traditional incorporational errors also induces similar errors by an additional mechanism - due to a facilitated tautomerization of the wobble base pair Ade.DCyt (compared to the same pair Ade.Cyt) to a mispair Ade.DCyt* which is quasirisomorphic Watson-Crick base pair. Moreover, the obtained results allowed interpreting non-inconsistently the existing experimental NMR data.
Assuntos
Antimetabólitos , Citosina , Replicação do DNA , Adenina/metabolismo , Antimetabólitos/química , Antimetabólitos/metabolismo , Pareamento Incorreto de Bases , Cristalografia por Raios X , Citosina/análogos & derivados , Citosina/metabolismo , DNA/química , DNA/metabolismo , Elétrons , Guanina/metabolismo , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação de Ácido Nucleico , Teoria Quântica , TermodinâmicaRESUMO
Purine-purine mispairs of DNA (thus involving template base in anti-conformation along the glycosidic bond and base of the incoming nucleotide - in syn-conformation) leading to pyrimidine-purine "transversions"-type point mutations were revealed and characterized at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in vacuum approach adequately modeling hydrophobic environment of the active centre of high-fidelity replicative DNA-polymerases.
Assuntos
Pareamento Incorreto de Bases , DNA Polimerase Dirigida por DNA/metabolismo , DNA/química , Purinas/metabolismo , Pirimidinas/metabolismo , DNA/metabolismo , Replicação do DNA , DNA Polimerase Dirigida por DNA/química , Elétrons , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Modelos Moleculares , Conformação de Ácido Nucleico , Teoria Quântica , TermodinâmicaRESUMO
A novel physico-chemical mechanism of the Watson-Crick DNA base pair Gua.Cyt tautomerization Gua.Cyt*<---->Gua.Cyt<---->Gua*.Cyt (mutagenic tautomers of bases are marked by asterisks) have been revealed and realized in a pathway of single proton transfer through two mutual isoenergetic transition states with Gibbs free energy of activation 30.4 and 30.6 kcal/mol and they are ion pairs stabilized by three (N2H...N3, N1H...N4- and O6+H...N4-) and five (N2H...O2, N1H...O2, N1H...N3, O6+H...N4- and 06+H...N4-) H-bonds accordingly. Stable base pairs Gua-Cyt* and Gua*.Cyt which dissociate comparably easy into monomers have acceptable relative Gibbs energies--12.9 and 14.3 kcal/mol--for the explanation of the nature of the spontaneous transitions of DNA replication. Results are obtained at the MP2/6-311++G(2df,pd)//B3LYP/6-31 1++G(d,p) level of theory in vacuum approach.