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Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center | Brovarets O.O.,Taras Shevchenko National University | Yurenko Y.P.,NASU Institute of Molecular Biology and Genetics | And 5 more authors.
Journal of Biomolecular Structure and Dynamics | Year: 2014

This study aims to cast light on the physico-chemical nature and energetic of the non-conventional CH⋯O/N H-bonds in the biologically important natural nucleobase pairs using a comprehensive quantum-chemical approach. As a whole, the 36 biologically important pairs, involving canonical and rare tautomers of nucleobases, were studied by means of all available up-to-date state-of-the-art quantum-chemical techniques along with quantum theory "Atoms in molecules" (QTAIM), Natural Bond Orbital (NBO) analysis, Grunenbergs compliance constants theory, geometrical and vibrational analyses to identify the CH⋯O/N interactions, reveal their physico-chemical nature and estimate their strengths as well as contribution to the overall base-pairs stability. It was shown that all the 38 CH⋯O/N contacts (25 CH⋯O and 13 CH⋯N H-bonds) completely satisfy all classical geometrical, electron-topological, in particular Baders and "two-molecule" Koch and Popeliers, and vibrational criteria of H-bonding. The positive values of Grunenbergs compliance constants prove that the CH⋯O/N contacts in nucleobase pairs are stabilizing interactions unlike electrostatic repulsion and anti-H-bonds. NBO analysis indicates the electron density transfer from the lone electron pair of the acceptor atom (O/N) to the antibonding orbital corresponding to the donor group σ*(CH). Moreover, significant increase in the frequency of the out-of-plane deformation modes γ (CH) under the formation of the CH⋯O (by 17.2/81.3/10.8/84.7 cm-1) and CH⋯N (by 32.7/85.9/9.0/77.9 cm-1) H-bonds at the density functional theory (DFT)/second-order Møller-Plesset (MP2) levels of theory, respectively, and concomitant changes of their intensities can be considered as reliable indicators of H-bonding. The strengths of the CH⋯O/N interactions, evaluated by means of Espinosa-Molins-Lecomte formula, lie within the range 0.45/3.89/0.62/4.10 kcal/mol for the CH⋯O H-bonds and 1.45/3.17/1.70/3.43 kcal/mol for the CH⋯N H-bonds at the DFT/MP2 levels of theory, respectively. We revealed high linear mutual correlations between the H-bond energy and different physico-chemical parameters of the CH⋯O/N H-bonds. Based on these observations, the authors asserted that the most reliable descriptors of the H-bonding are the electron density ρ at the ⋯/N H-bond critical points and the NBO calculated stabilization energy E(2). The linear dependence of the H-bond energy ECH⋯O/N (in kcal/mol) on the electron density ρ (in atomic units) was established (DFT/MP2): ECH⋯O = 248.501ρ-0.367/260.518ρ-0.373 and ECH⋯N = 218.125ρ-0.339/243.599ρ-0.441. Red-shifted and blue-shifted CH⋯O/N H-bonds behave in a similar way and can be described with the same fit parameters. It was found that the A-U HH2 and U-U3 nucleobase pairs are stabilized solely by the CH⋯O/N H-bonds. At the same time, in the A-U HH1, A-U HH2, A-Asyn1, A-Asyn2, A-Asyn3, A-A4, A-G1, A-G2, G-U1, G-U2, G-U 3, G-C HH1, U-U1, U-U2, U-U 3 and A-C nucleobase pairs the CH⋯O/N H-bonds play a prominent role (>30%) in their stabilization. We suppose that unconventional CH⋯O/N H-bond plays the role of the third "fulcrum", ensuring structurally dynamic similarity of the isomorphic base pairs of different origin, which are incorporated equally well into the structure of the DNA double helix. © 2013 Taylor & Francis.


Ponomareva A.G.,NASU Institute of Molecular Biology and Genetics | Yurenko Y.P.,NASU Institute of Molecular Biology and Genetics | Yurenko Y.P.,Research and Educational Center | Yurenko Y.P.,Taras Shevchenko National University | And 5 more authors.
Physical Chemistry Chemical Physics | Year: 2012

A comprehensive quantum-chemical conformational analysis of two nucleoside analogues, 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U) and 2′,3′-didehydro-2′,3′-dideoxycytidine (d4C), is reported. The electronic structure calculations were performed at the MP2/6-311++G(d,p)//B3LYP/6-31++G(d,p) level of theory. It was found that d4U and d4C adopt 20 conformers and 19 conformers, respectively, which correspond to local minima on the respective potential energy landscapes. QTAIM and NBO analyses show that the d4U and d4C conformers are stabilised by a complicated network of specific intramolecular interactions, which includes conventional (OH...O) and non-conventional (CH...O, CH...HC) H-bonds as well as closed-shell van der Waals (C...O) contacts. A satisfactory linear correlation was found between Grunenberg's compliance constants for closed-shell intramolecular interactions and their energy. It is shown that there are no conformational obstacles for incorporation of d4U and d4C into the double helical A and B forms of DNA. The less pronounced biological activity of d4U as compared to 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) is most likely due to the presence of the bulky methyl group at the 5-position of d4T, which can be recognised by target enzymes. © 2012 the Owner Societies.


Nikolaienko T.Y.,Taras Shevchenko National University | Bulavin L.A.,Taras Shevchenko National University | Hovorun D.M.,NASU Institute of Molecular Biology and Genetics | Hovorun D.M.,Research and Educational Center | Hovorun D.M.,Taras Shevchenko National University
Physical Chemistry Chemical Physics | Year: 2012

Physical properties of over 8000 intramolecular hydrogen bonds (iHBs), including 2901 ones of the types OH⋯O, OH⋯N, NH⋯O and OH⋯C, in 4244 conformers of the DNA-related molecules (four canonical 2′-deoxyribonucleotides, 1,2-dideoxyribose-5-phosphate, and 2-deoxy-d-ribose in its furanose, pyranose and linear forms) have been investigated using quantum theory of atoms in molecules (QTAIM) and vibrational analysis. It has been found that for all iHBs with positive red-shift of the proton donating group stretching frequency the shift value correlates with ρ cp - the electron charge density at the (3,-1)-type bond critical point. Combining QTAIM and spectroscopic data new relationships for estimation of OH⋯O, OH⋯N, NH⋯O and OH⋯C iHB enthalpy of formation (kcal mol -1) with RMS error below 0.8 kcal mol -1 have been established: E OH⋯O = -3.09 + 239·ρ cp, E OH⋯N = 1.72 + 142·ρ cp, E NH⋯O = -2.03 + 225·ρ cp, E OH⋯C = -0.29 + 288·ρ cp, where ρ cp is in e a 0 -3 (a 0 - the Bohr radius). It has been shown that XH⋯Y iHBs with red-shift values over 40 cm -1 are characterized by the following minimal values of the XHY angle, ρ cp and ∇ 2ρ cp: 112°, 0.005 e a 0 -3 and 0.016 e a 0 -5, respectively. New relationships have been used to reveal the strongest iHBs in canonical 2′-deoxy- and ribonucleosides and the O 5′H⋯N 3 H-bond in ribonucleoside guanosine was found to have the maximum energy (8.1 kcal mol -1). © 2012 the Owner Societies.


Brovarets' O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets' O.O.,Research and Educational Center | Brovarets' O.O.,Taras Shevchenko National University | Zhurakivsky R.O.,NASU Institute of Molecular Biology and Genetics | And 4 more authors.
Chemical Physics Letters | Year: 2013

We showed that biologically important planar Hyp*· Hyp base pair (Cs) formed by the enol and keto tautomers of the hypoxanthine tautomerises via the synchronous concerted mechanism through the TS (C2v). The five key points were detected and completely investigated along the IRC of the Hyp*· Hyp † Hyp·Hyp* tautomerisation via the DPT. It was found that intermolecular antiparallel O6H.O6 and N1H.N1 H-bonds are cooperative and mutually reinforce each other. It was proved that the Hyp *·Hyp/Hyp·Hyp* base pair is dynamically stable structure with a lifetime 8.2 × 10-12 s and all its six low-frequency intermolecular vibrations are able to develop during this period of time. © 2013 Elsevier B.V. All rights reserved.


Nikolaienko T.Yu.,Taras Shevchenko National University | Bulavin L.A.,Taras Shevchenko National University | Hovorun D.M.,NASU Institute of Molecular Biology and Genetics | Hovorun D.M.,Research and Educational Center | Hovorun D.M.,Taras Shevchenko National University
Physical Chemistry Chemical Physics | Year: 2012

Relaxed force constants (RFC) and vibrational root-mean-square (VRMS) deviations are used for comparative characterization of mechanical properties of canonical 2′-deoxyribonucleosides (2DRs) and 1,2-dideoxyribose molecule, their model sugar residue. It has been shown that RFC and VRMS should be preferred over traditional force constants when one needs to obtain the quantitative measure of the 'collective' parameter flexibility (furanose sugar pseudorotation phase P in particular) and compare it with classical torsion angles (β, γ, ε, χ). It has been found that torsions ε and β determining the 2DRs backbone hydroxyl orientations are as soft as the pseudorotation phase P with RFC values within 1-10 kcal mol-1 rad-2 depending on conformation. Torsion γ is the most rigid one with RFC 15-30 kcal mol-1 rad-2, while the glycosidic torsion χ is characterized by intermediate values of RFC (typically 5-10 kcal mol-1 rad-2) and its RFC changes by 10 times, depending on the furanose sugar conformation (Kχ ≈ 3 kcal mol-1 rad-2 in B- vs. Kχ ≈ 21 kcal mol-1 rad-2 in A-DNA-like conformation of 2′-deoxycytidine). Quantum zero-point motion of the nuclei makes the dominant contribution to VRMS deviations of molecules structural parameters: 9-22°for β, ε and P, 5-7°for γ and χ at the temperature of 0 K, and 15-38°for β, ε and P, 9-26°for γ and χ at the room temperature (298.15 K). Obtained results can be used in constructing simple dynamical models of the DNA fragments. © 2012 the Owner Societies.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center | 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: 2014

Trying to answer the question posed in the title, we have carried out a detailed theoretical investigation of the biologically important mechanism of the tautomerization of the A·T Watson-Crick DNA base pair, information that is hard to establish experimentally. By combining theoretical investigations at the MP2 and density functional theory levels of QM theory with quantum theory of atoms in molecules analysis, the tautomerization of the A·T Watson-Crick base pair by the double proton transfer (DPT) was comprehensively studied in vacuo and in the continuum with a low dielectric constant (ε = 4) corresponding to a hydrophobic interfaces of protein-nucleic acid interactions. Based on the sweeps of the electron-topological, geometric, and energetic parameters, which describe the course of the tautomerization along its intrinsic reaction coordinate (IRC), it was proved that the A·T → A*·T* tautomerization through the DPT is a concerted (i.e. the pathway without an intermediate) and asynchronous (i.e. protons move with a time gap) process. The limiting stage of this phenomenon is the final PT along the N6H...O4 hydrogen bond (H-bond). The continuum with ε = 4 does not affect qualitatively the course of the tautomerization reaction: similar to that observed in vacuo, it proceeds via a concerted asynchronous process with the same structure of the transition state (TS). For the first time, the nine key points along the IRC of the A·T base pair tautomerization, which could be considered as electron-topological "fingerprints" of a concerted asynchronous process of the tautomerization via the DPT, have been identified and fully characterized. These nine key points have been used to define the reactant, TS, and product regions of the DPT in the A·T base pair. Considering the energy dependence of each of the three H-bonds, which stabilize the Watson-Crick and Löwdins base pairs, along the IRC of the tautomerization, it was found that all these H-bonds in the A·T base pair are cooperative, reinforcing each other, whereas the C2H...O2 H-bond in the A*·T* base pair behaves anticooperatively, in other words it gets weakened while two others get strengthened. From a quantum-mechanical point of view, the A*· T* Löwdins base pair appeared to be dynamically unstable because the electronic energy of the back-reaction barrier of the A·T → A*·T* tautomerization does not exceed zero-point vibrational energy associated with the mode for which vibrational frequency becomes imaginary in the TS of tautomerization. Additionally, it was demonstrated using the conductor-like polarizable continuum model that the effects of biomolecular environment (ε = 4) cannot ensure dynamic stabilization of the A*·T* Löwdins base pair. These findings, together with data available from the literature, indicate that the tautomerization of the A·T Watson-Crick base pair to the A*·T* Löwdins base pair through the DPT cannot be a source of spontaneous point errors that occur during DNA replication. © 2013 Taylor & Francis.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center | Brovarets O.O.,Taras Shevchenko National University | Yurenko Y.P.,Research and Educational Center | And 5 more authors.
Journal of Biomolecular Structure and Dynamics | Year: 2012

Ab initio quantum-chemical study of specific point contacts of replisome proteins with DNA modeled by acetic acid with canonical and mutagenic tautomers of DNA bases methylated at the glycosidic nitrogen atoms was performed in vacuo and continuum with a low dielectric constant (ε ∼ 4) corresponding to a hydrophobic interface of protein-nucleic acid interaction. All tautomerized complexes were found to be dynamically unstable, because the electronic energies of their back-reaction barriers do not exceed zero-point vibrational energies associated with the vibrational modes whose harmonic vibrational frequencies become imaginary in the transition states of the tautomerization reaction. Additionally, based on the physicochemical arguments, it was demonstrated that the effects of biomolecular environment cannot ensure dynamic stabilization. This result allows suggesting that hypothetically generated by DNA-binding proteins of replisome rare tautomers will have no impact on the total spontaneous mutation due to the low reverse barrier allowing a quick return to the canonical form. Copyright © 2012 Taylor & Francis.


Brovarets' O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets' O.O.,Research and Educational Center | Brovarets' O.O.,Taras Shevchenko National University | Hovorun D.M.,NASU Institute of Molecular Biology and Genetics | And 2 more authors.
Physical Chemistry Chemical Physics | Year: 2013

A theoretical study of tautomerisation of the biologically important cytosine·cytosine* (C·C*) DNA mismatch with a propeller-like structure (C4N3N3C4 = 32.4°; C1 symmetry) and cis-oriented N1H glycosidic bonds, formed by the amino and imino tautomers of the C nucleobase, via the asynchronous concerted double proton transfer (DPT) along two H-bonds through the transition state (TS C·C*↔C*·C) (C4N3N3C4 = 48.5°; C1 symmetry) into the C*·C mispair was carried out for the first time. It was established that the C·C*/C*·C DNA base mispair is associated by the antiparallel N4H⋯N4 (6.66 kcal mol-1), N3H⋯N3 (6.47 kcal mol-1) H-bonds and the O2⋯O2 van der Waals (vdW) contact (0.33 kcal mol-1), while the zwitterionic TSC·C*↔C*·C is stabilized by the parallel N4+H⋯N4- (13.55 kcal mol-1), N3+H⋯N3- (13.20 kcal mol -1) H-bonds and the O2+⋯O2- vdW contact (0.60 kcal mol-1). It was shown that the C·C* ↔ C*·C tautomerisation via the DPT is assisted by the O2⋯O2 vdW contact, that in contrast to the two others N4H⋯N4 and N3H⋯N3 H-bonds exists along the entire intrinsic reaction coordinate (IRC) range. The positive values of the Grunenberg's compliance constants (30.919 and 21.384 Å mdyn-1 for C·C*/C*·C and TS C·C*↔C*·C, respectively) indicate that the O2⋯O2 vdW contact is a stabilizing closed-shell interaction. It was found that the middle N3H⋯N3 H-bond is anti-cooperative with the upper N4H⋯N4 H-bond and cooperative with the lower O2⋯O2 vdW contact. The 9 key points, which can be considered as electron-topological "fingerprints" of the asynchronous concerted C·C* ↔ C*·C tautomerisation process via the DPT were revealed along the IRC and examined in detail. It was shown that the C·C*/ C*·C base mispair is a thermodynamically and dynamically stable structure. Its lifetime is equal to 1.53 × 10-7 s at the MP2/cc-pVQZ//B3LYP/6-311++G(d,p) level of theory in vacuum. All 6 low-frequency intermolecular vibrations are able to develop during this time span. © 2013 the Owner Societies.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center | 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: 2013

The molecular structures, relative stability order, and dipole moments of a complete family of 21 planar hypoxanthine (Hyp) prototropic molecular-zwitterionic tautomers including ylidic forms were computationally investigated at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in vacuum and in three different surrounding environments: continuum with a low dielectric constant (ε = 4) corresponding to a hydrophobic interface of protein-nucleic acid interactions, dimethylsulfoxide (DMSO), and water. The keto-N1HN7H tautomer was established to be the global minimum in vacuum and in continuum with ε = 4, while Hyp molecule exists as a mixture of the keto-N1HN9H and keto-N1HN7H tautomers in approximately equal amounts in DMSO and in water at T = 298.15 K. We found out that neither intramolecular tautomerization by single proton transfer in the Hyp base, nor intermolecular tautomerization by double proton transfer in the most energetically favorable Hyp·Hyp homodimer (symmetry C2h), stabilized by two equivalent N1H...O6 H-bonds, induces the formation of the enol tautomer (marked with an asterisk) of Hyp with cis-oriented O6H hydroxyl group relative to neighboring N1C6 bond. We first discovered a new scenario of the keto-enol tautomerization of Hyp · Hyp homodimer (C2h) via zwitterionic near-orthogonal transition state (TS), stabilized by N1+H...N1- and O6+H...N 1- H-bonds, to heterodimer Hyp*·Hyp (Cs), stabilized by O6H...O6 and N1H...N1 H-bonds. We first showed that Hyp* · Thy mispair (Cs), stabilized by O6H...O4, N3H...N1, and C2H...O2 H-bonds, mimicking Watson-Crick base pairing, converts to the wobble Hyp* · Thy base pair (Cs), stabilized by N3H...O6 and N1H...O2 H-bonds, via high- and low-energy TSs and intermediate Hyp · Thy*, stabilized by O4H...O6, N1H...N3, and C2H...O2 H-bonds. The most energetically favorable TS is the zwitterionic pair Hyp+ · Thy- (Cs), stabilized by O6+H...O4-, O6+H...N3-, N1+H... N3-, and N1+H...O2- H-bonds. The authors expressed and substantiated the hypothesis, that the keto tautomer of Hyp is a mutagenic compound, while enol tautomer Hyp* does not possess mutagenic properties. The lifetime of the nonmutagenic tautomer Hyp* exceeds by many orders the time needed to complete a round of DNA replication in the cell. For the first time purine-purine planar H-bonded mispairs containing Hyp in the anti-orientation with respect to the sugar moiety - Hyp · Adesyn, Hyp · Gua*syn, and Hyp · Gua*syn, that closely resembles the geometry of the Watson-Crick base pairs, have been suggested as the source of transversions. An influence of the surrounding environment (ε = 4) on the stability of studied complexes and corresponding TSs was estimated by means of the conductor-like polarizable continuum model. Electron-topological, structural, vibrational, and energetic characterictics of all conventional and nonconventional H-bonds in the investigated structures are presented. Presented data are key to understanding elementary molecular mechanisms of mutagenic action of Hyp as a product of the adenine deamination in DNA. © 2012 Taylor & Francis.


Brovarets O.O.,NASU Institute of Molecular Biology and Genetics | Brovarets O.O.,Research and Educational Center | 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: 2014

The ground-state tautomerization of the G·C Watson-Crick base pair by the double proton transfer (DPT) was comprehensively studied in vacuo and in the continuum with a low dielectric constant (ε = 4), corresponding to a hydrophobic interface of protein-nucleic acid interactions, using DFT and MP2 levels of quantum-mechanical (QM) theory and quantum theory "Atoms in molecules" (QTAIM). Based on the sweeps of the electron-topological, geometric, polar, and energetic parameters, which describe the course of the G·C↔G*·C* tautomerization (mutagenic tautomers of the G and C bases are marked with an asterisk) through the DPT along the intrinsic reaction coordinate (IRC), it was proved that it is, strictly speaking, a concerted asynchronous process both at the DFT and MP2 levels of theory, in which protons move with a small time gap in vacuum, while this time delay noticeably increases in the continuum with ε = 4. It was demonstrated using the conductor-like polarizable continuum model (CPCM) that the continuum with ε = 4 does not qualitatively affect the course of the tautomerization reaction. The DPT in the G·C Watson-Crick base pair occurs without any intermediates both in vacuum and in the continuum with ε = 4 at the DFT/MP2 levels of theory. The nine key points along the IRC of the G·C base pair tautomerization, which could be considered as electron-topological "fingerprints" of a concerted asynchronous process of the tautomerization via the DPT, have been identified and fully characterized. These key points have been used to define the reactant, transition state, and product regions of the DPT reaction in the G·C base pair. Analysis of the energetic characteristics of the H-bonds allows us to arrive at a definite conclusion that the middle N1H.N3/N3H.N1 and the lower N2H.O2/N2H.O2 parallel H-bonds in the G·C↔G*·C*·C* base pairs, respectively, are anticooperative, that is, the strengthening of the middle H-bond is accompanied by the weakening of the lower H-bond. At that point, the upper N4H.O6 and O6H.N4 H-bonds in the G·C and G*·C* base pairs, respectively, remain constant at the changes of the middle and the lower H-bonds at the beginning and at the ending of the G·C↔G*·C* tautomerization. Aiming to answer the question posed in the title of the article, we established that the G*·C* Löwdin's base pair satisfies all the requirements necessary to cause point mutations in DNA except its lifetime, which is much less than the period of time required for the replication machinery to forcibly dissociate a base pair into the monomers (several ns) during DNA replication. So, from the physicochemical point of view, the G*·C* Löwdin's base pair cannot be considered as a source of point mutations arising during DNA replication. © 2013 Taylor & Francis.

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