Research and Educational Center State Key Laboratory of Molecular and Cell Biology

Kiev, Ukraine

Research and Educational Center State Key Laboratory of Molecular and Cell Biology

Kiev, Ukraine
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Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center State Key Laboratory of Molecular and Cell Biology | Brovarets O.O.,Taras Shevchenko National University | Zhurakivsky R.O.,NASU Institute of Molecular Biology and Genetics | And 4 more authors.
Physical Chemistry Chemical Physics | Year: 2014

We have scrupulously explored the tautomerisation mechanism via the double proton transfer of the A*·Asyn Topal-Fresco base mispair (Cs symmetry), formed by the imino and amino tautomers of the adenine DNA base in the anti- and syn-conformations, respectively, bridging quantum-mechanical calculations with Bader's quantum theory of atoms in molecules. It was found that the A*·Asyn ↔ A·A*syn tautomerisation is the asynchronous concerted process. It was established that the A*·Asyn DNA mismatch is stabilized by the N6H⋯N6 (6.35) and N1H⋯N7 (6.17) hydrogen (H) bonds, whereas the A·A*syn base mispair (Cs) by the N6H⋯N6 (8.82) and N7H⋯N1 (9.78) H-bonds and the C8H⋯HC2 HH-bond (0.30 kcal mol-1). Using the sweeps of the energies of the intermolecular H-bonds, it was observed that the N6H⋯N6 and N1H⋯N7/N7H⋯N1 H-bonds are anti-cooperative and mutually weaken each other in the A*·Asyn and A·A*syn mispairs. It was revealed that the A·A*syn DNA mismatch is a dynamically unstable structure with a short lifetime of 1.12 × 10-13 s and any of its 6 low-frequency intermolecular vibrations can develop during this period of time. This observation makes it impossible to change the tautomeric status of the A bases upon the dissociation of the A*·Asyn base mispair into the monomers during DNA replication. © 2014 the Owner Societies.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center State Key Laboratory of Molecular and Cell Biology | Brovarets O.O.,Taras Shevchenko National University
Ukrain'skyi Biokhimichnyi Zhurnal | Year: 2013

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.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center State Key Laboratory of Molecular and Cell Biology | Brovarets O.O.,Taras Shevchenko National University | Zhurakivsky R.O.,NASU Institute of Molecular Biology and Genetics | And 4 more authors.
Journal of Molecular Modeling | Year: 2013

The biologically important tautomerization of the Hyp·Cyt, Hyp·Thy and Hyp·Hyp base pairs to the Hyp*·Cyt* , Hyp·Thy*and Hyp*·Hyp*base pairs, respectively, by the double proton transfer (DPT) was comprehensively studied in vacuo and in the continuum with a low dielectric constant (ε = 4) corresponding to hydrophobic interfaces of protein-nucleic acid interactions by combining theoretical investigations at the B3LYP/6-311++G(d,p) level of QM theory with QTAIM topological analysis. Based on the sweeps of the energetic, electron-topological, geometric and polar parameters, which describe the course of the tautomerization along the intrinsic reaction coordinate (IRC), it was proved that the tautomerization through the DPT is concerted and asynchronous process for the Hyp·Cyt and Hyp*·Thy base pairs, while concerted and synchronous for the Hyp·Hyp homodimer. The continuum with ε = 4 does not affect qualitatively the course of the tautomerization reaction for all studied complexes. The nine key points along the IRC of the Hyp·Cyt↔Hyp*·Cyt*and Hyp*·Thy↔ Hyp·Thy*tautomerizations and the six key points of the Hyp·Hyp↔Hyp*·Hyp*tautomerization have been identified and fully characterized. These key points could be considered as electron-topological "fingerprints" of concerted asynchronous (for Hyp·Cyt and Hyp*·Thy) or synchronous (for Hyp·Hyp) tautomerization process via the DPT. It was found, that in the Hyp*·Cyt*, Hyp·Thy*, Hyp·Hyp and Hyp*·Hyp*base pairs all H-bonds are significantly cooperative and mutually reinforce each other, while the C2H.O2 H-bond in the Hyp·Cyt base pair and the O6H.O4 H-bond in the Hyp*·Thy base pair behave anti-cooperatively, i.e., they become weakened, while two others become strengthened. © 2012 Springer-Verlag Berlin Heidelberg.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center State Key Laboratory of Molecular and Cell Biology | Brovarets O.O.,Taras Shevchenko National University | Zhurakivsky R.O.,NASU Institute of Molecular Biology and Genetics | And 4 more authors.
Journal of Molecular Modeling | Year: 2013

Combining quantum-mechanical (QM) calculations with quantum theory of atoms in molecules (QTAIM) and using the methodology of sweeps of the energetic, electron-topological, geometric and polar parameters, which describe the course of the tautomerization along the intrinsic reaction coordinate (IRC), we showed for the first time that the biologically important A·A*base pair (Cs symmetry) formed by the amino and imino tautomers of adenine (A) tautomerizes via asynchronous concerted double proton transfer (DPT) through a transition state (TS), which is the A+·A- zwitterion with the separated charge, with Cs symmetry. The nine key points, which can be considered as electron-topological "fingerprints" of the asynchronous concerted A·A*↔A*·A tautomerization process via the DPT, were detected and completely investigated along the IRC of the A·A*↔A*·A tautomerization. Based on the sweeps of the H-bond energies, it was found that intermolecular antiparallel N6⋯N6 (7.01 kcal mol-1) and N1Hâ̄N1 (6.88 kcal mol-1) H-bonds are significantly cooperative and mutually reinforce each other. It was shown for the first time that the A·A*↔A*·A tautomerization is assisted by the third C2Hâ̄HC2 dihydrogen bond (DHB), which, in contrast to the two others N6Hâ̄N6 and N1Hâ̄N1 H-bonds, exists within the IRC range from -2.92 to 2.92 Å. The DHB cooperatively strengthens, reaching its maximum energy 0.42 kcal mol-1 at IRC = -0.52 Å and minimum energy 0.25 kcal mol-1 at IRC = -2.92 Å, and is accompanied by strengthening of the two other aforementioned classical H-bonds. We established that the C2Hâ̄HC2 DHB completely satisfies the electron-topological criteria for H-bonding, in particular Bader's and all eight "two- molecule" Koch and Popelier's criteria. The positive value of the Grunenberg's compliance constant (5.203 Å/mdyn) at the TS A·A*↔A*·A proves that the C2Hâ̄HC2 DHB is a stabilizing interaction. NBO analysis predicts transfer of charge from σ(C2-H) bonding orbital to σ*(H-C2) anti-bonding orbital; at this point, the stabilization energy E(2) is equal to 0.19 kcal mol-1 at the TS A·A*↔A*·A. © 2013 Springer-Verlag Berlin Heidelberg.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center State Key Laboratory of Molecular and Cell Biology | Brovarets O.O.,Taras Shevchenko National University | Zhurakivsky R.O.,NASU Institute of Molecular Biology and Genetics | And 4 more authors.
Molecular Physics | Year: 2014

We provide a pathway for the tautomerisation of the biologically important hypoxanthine·adenine (Hyp·Ade) nucleobase pair (Cs) formed by the keto tautomer of the Hyp and the amino tautomer of the Ade into the Hyp*·Ade* base pair (Cs) formed by the enol tautomer of the Hyp and the imino tautomer of the Ade by applying quantum-mechanical calculations and Bader's Quantum Theory of Atoms in Molecules analysis. It was found out that the dipole active Hyp·Ade↔Hyp*·Ade* tautomerisation occurs via the asynchronous concerted double proton transfer (DPT) through the TSHyp·Ade↔Hyp*·Ade* (Cs). Based on the sweeps of the energies of the intermolecular H-bonds along the intrinsic reaction coordinate, it was established that the N6H···O6 H-bond (5.40) is cooperative with the N1H···N1 H-bond (6.99) in the Hyp·Ade base pair, as well as the O6H···N6 H-bond (11.50) is cooperative with the N1H···N1 H-bond (7.28 kcal·mol-1) in the Hyp*·Ade* base pair, mutually strengthening each other. The Hyp*·Ade* base pair possesses an extremely short lifetime 2.68·10-14 s, which is predetermined by the negative value of the Gibbs free energy of the reverse barrier of its tautomerisation, and all of the six low-frequency intermolecular vibrations cannot develop during this period of time. Consequently, the Hyp·Ade→Hyp*·Ade* DPT tautomerisation cannot serve as a source of the rare tautomers of the bases. © 2014 Taylor & Francis.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center State Key Laboratory of Molecular and Cell Biology | Brovarets O.O.,Taras Shevchenko National University
Ukrain'skyi Biokhimichnyi Zhurnal | Year: 2013

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 (Löwdin'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-O2 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.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center State Key Laboratory of Molecular and Cell Biology | Brovarets O.O.,Taras Shevchenko National University | Hovorun D.M.,NASU Institute of Molecular Biology and Genetics | And 2 more authors.
Journal of Biomolecular Structure and Dynamics | Year: 2015

It was established for the first time by DFT and MP2 quantum-mechanical (QM) methods either in vacuum, so in the continuum with a low dielectric constant (ε = 4), typical for hydrophobic interfaces of specific protein-nucleic acid interactions, that the repertoire for the tautomerisation of the biologically important adenine·cytosine∗ (A·C∗) mismatched DNA base pair, formed by the amino tautomer of the A and the imino mutagenic tautomer of the C, into the A∗·C base mispair (G = 2.72 kcal mol-1 obtained at the MP2 level of QM theory in the continuum with ε = 4), formed by the imino mutagenic tautomer of the A and the amino tautomer of the C, proceeds via the asynchronous concerted double proton transfer along two antiparallel H-bonds through the transition state (TSA·C∗虠A∗·C). The limiting stage of the A·C∗→A∗·C tautomerisation is the final proton transfer along the intermolecular N6H···N4 H-bond. It was found that the A·C∗/A∗·C DNA base mispairs with Watson-Crick geometry are associated by the N6HN4/N4HN6, N3HN1/N1HN3 and C2HO2 H-bonds, respectively, while the TSA·C∗虠A∗·C is joined by the N6-H-N4 covalent bridge and the N1HN3 and C2HO2 H-bonds. It was revealed that the A·C∗虠A∗·C tautomerisation is assisted by the true C2HO2 H-bond, that in contrast to the two others conventional H-bonds exists along the entire intrinsic reaction coordinate (IRC) range herewith becoming stronger at the transition from vacuum to the continuum with ε = 4. To better understand the behavior of the intermolecular H-bonds and base mispairs along the IRC of the A·C∗虠A∗·C tautomerisation, the profiles of their electron-topological, energetical, geometrical, polar and charge characteristics are reported in this study. It was established based on the profiles of the H-bond energies that all three H-bonds are cooperative, mutually strengthening each other. The nine key points, providing a detailed physicochemical picture of the A·C∗虠A∗·C tautomerisation, were revealed and thoroughly examined along the IRC. It was shown that the A∗·C base mispair with the population ~1 % obtained at the MP2 level of QM theory in the continuum with ε = 4 is thermodynamically and dynamically stable structure. Its lifetime was calculated to be 5.76·10-10 s at the MP2 level of QM theory in the continuum with ε = 4. This lifetime, from the one side, enables all six low-frequency intermolecular vibrations to develop, but, from the other side, it is by order less than the time (several ns) required for the replication machinery to forcibly dissociate a base pair into the monomers during DNA replication. This means that the A∗·C base mispair "slips away from the hands" of the replication machinery into the A·C∗ mismatched base pair. Consequently, the authors came to the conclusion that exactly the A·C∗ base mispair is an active player of the point mutational events and is effectively dissociated by the replication machinery into the A and C∗ monomers in contrast to the A∗·C base mispair, playing the mediated role of a provider of the A·C∗ base mispair in DNA that is synthesised. © 2013 Taylor & Francis.

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