Physico-chemical profiles of the wobble ↔ Watson-Crick G*·2AP(w) ↔ G·2AP(WC) and A·2AP(w) ↔ A*·2AP(WC) tautomerisations: a QM/QTAIM comprehensive survey.

This study is intended to clarify in detail the tautomeric transformations of the wobble (w) G*·2AP(w) and A·2AP(w) nucleobase mispairs involving 2-aminopurine (2AP) into the Watson-Crick (WC) G·2AP(WC) and A*·2AP(WC) base mispairs (asterisks denote mutagenic tautomers of the DNA bases), respectively, by quantum-mechanical methods and Bader's Quantum Theory of Atoms in Molecules. Our previously reported methodology has been used, which allows the evolution of the physico-chemical parameters to be tracked along the entire internal reaction coordinate (IRC), not exclusively in the stationary states of these reactions. These biologically important G*·2AP(w) ↔ G·2AP(WC) and A·2AP(w) ↔ A*·2AP(WC) w ↔ WC tautomerisations, which are involved in mutagenic tautomerically-conformational pathways, determine the origin of the transitions and transversions induced by 2AP. In addition, it is established that they proceed through planar, highly stable, zwitterionic transition states and they exhibit similar physico-chemical profiles and stages of sequential intrapair proton transfer, followed by spatial rearrangement of the nucleobases relative to each other within the base pairs. These w ↔ WC tautomerisations occur non-dissociatively and are accompanied by a significant alteration in geometry (from wobble to Watson-Crick and vice versa) and redistribution of the specific intermolecular interactions, which can be divided into 10 patterns including AHB H-bonds and loosened A-H-B covalent bridges along the IRC of tautomerisation. Based on the redistribution of the geometrical and electron-topological parameters of the intrapair hydrogen bonds, exactly 9 key points have been allocated to characterize the evolution of these reactions.

Tautomeric transition between wobble A·C DNA base mispair and Watson-Crick-like A·C* mismatch: microstructural mechanism and biological significance.

Here, we use MP2/DFT quantum-chemical methods combined with Quantum Theory of Atoms in Molecules to study the tautomeric transition between wobble A·C(w) mismatch and Watson-Crick-like A·C*(WC) base mispair, proceeding non-dissociatively via sequential proton transfer between bases through the planar, highly stable and zwitterionic TS(A∙C-)(A∙C(W)<-->A∙C&(WC)) transition state joined by the participation of (A)N6(+)H∙∙∙N4(-)(C), (A)N1(+)H∙∙∙N4(-)(C) and (A)C2(+)H∙∙∙N3(-)(C) H-bonds. Notably, the A·C(w) ↔ A·C*(WC) tautomerization reaction is accompanied by 10 unique patterns of the specific intermolecular interactions that consistently replace each other. Our data suggest that biologically significant A·C(w) → A·C*(WC) tautomerization is a kinetically controlled pathway for formation of the enzymatically competent Watson-Crick-like A·C*(WC) DNA base mispair in the essentially hydrophobic recognition pocket of the high-fidelity DNA-polymerase, responsible for the occurrence of spontaneous point AC/CA incorporation errors during DNA biosynthesis.

A novel conception for spontaneous transversions caused by homo-pyrimidine DNA mismatches: a QM/QTAIM highlight.

We have firstly shown that the T·T(w) and C·C(w) DNA mismatches with wobble (w) geometry stay in slow tautomeric equilibrium with short T·T*(WC) and C·C*(WC) Watson-Crick (WC) mispairs. These non-dissociative tautomeric rearrangements are controlled by the plane-symmetric, highly stable, highly polar and zwitterionic transition states. The obtained results allow us to understand in what way the T·T(w) and C·C(w) mismatches acquire enzymatically competent T·T*(WC) and C·C*(WC) conformations directly in the hydrophobic recognition pocket of a high-fidelity DNA-polymerase, thereby producing thermodynamically non-equilibrium spontaneous transversions. The simplest numerical estimation of the frequency ratio of the TT to CC spontaneous transversions satisfactorily agrees with experimental data.

Is the DPT tautomerization of the long A·G Watson-Crick DNA base mispair a source of the adenine and guanine mutagenic tautomers? A QM and QTAIM response to the biologically important question.

Herein, we first address the question posed in the title by establishing the tautomerization trajectory via the double proton transfer of the adenine·guanine (A·G) DNA base mispair formed by the canonical tautomers of the A and G bases into the A*·G* DNA base mispair, involving mutagenic tautomers, with the use of the quantum-mechanical calculations and quantum theory of atoms in molecules (QTAIM). It was detected that the A·G ↔ A*·G* tautomerization proceeds through the asynchronous concerted mechanism. It was revealed that the A·G base mispair is stabilized by the N6H···O6 (5.68) and N1H···N1 (6.51) hydrogen bonds (H-bonds) and the N2H···HC2 dihydrogen bond (DH-bond) (0.68 kcal·mol(-1) ), whereas the A*·G* base mispair-by the O6H···N6 (10.88), N1H···N1 (7.01) and C2H···N2 H-bonds (0.42 kcal·mol(-1) ). The N2H···HC2 DH-bond smoothly and without bifurcation transforms into the C2H···N2 H-bond at the IRC = -10.07 Bohr in the course of the A·G ↔ A*·G* tautomerization. Using the sweeps of the energies of the intermolecular H-bonds, it was observed that the N6H···O6 H-bond is anticooperative to the two others-N1H···N1 and N2H···HC2 in the A·G base mispair, while the latters are significantly cooperative, mutually strengthening each other. In opposite, all three O6H···N6, N1H···N1, and C2H···N2 H-bonds are cooperative in the A*·G* base mispair. All in all, we established the dynamical instability of the А*·G* base mispair with a short lifetime (4.83·10(-14) s), enabling it not to be deemed feasible source of the A* and G* mutagenic tautomers of the DNA bases. The small lifetime of the А*·G* base mispair is predetermined by the negative value of the Gibbs free energy for the A*·G* → A·G transition. Moreover, all of the six low-frequency intermolecular vibrations cannot develop during this lifetime that additionally confirms the aforementioned results. Thus, the A*·G* base mispair cannot be considered as a source of the mutagenic tautomers of the DNA bases, as the A·G base mispair dissociates during DNA replication exceptionally into the A and G monomers in the canonical tautomeric form.

DPT tautomerisation of the G·A(syn) and A*·G*(syn) DNA mismatches: a QM/QTAIM combined atomistic investigation.

By applying a combined QM and QTAIM atomistic computational approach we have established for the first time that the G·A(syn) and A*·G*(syn) DNA mismatches (rare tautomers are marked with an asterisk), causing spontaneous transversions with substantially various probabilities, radically differ from each other in their ability to tautomerise through the double proton transfer (DPT). The A*·G*(syn) mismatch tautomerises quite easily (ΔΔG(TS) ≈ 4·kT at room temperature) into the A·G*(syn) mismatch through the asynchronous concerted mechanism, whereas the G·A(syn) base mispair does not tautomerise via the DPT at all, since there is no local minimum corresponding to the tautomerised G*·A*(syn) mismatch on the potential energy surface. It was established that the A·G*(syn) base mispair is a dynamically unstable H-bonded complex with an extremely short lifetime of 2.17 × 10(-13) s. Consequently, the obtained results allow us to believe that spontaneous or forced dissociation of both the G·A(syn) and A*·G*(syn) DNA mismatches by the DNA-polymerase occurs with the preservation of the tautomeric status of the bases.

How does the long G·G* Watson-Crick DNA base mispair comprising keto and enol tautomers of the guanine tautomerise? The results of a QM/QTAIM investigation.

The double proton transfer (DPT) in the long G·G* Watson-Crick base mispair (|C6N1(G*)N1C6(G)| = 36.4°; C1 symmetry), involving keto and enol tautomers of the guanine (G) nucleobase, along two intermolecular neighboring O6H···O6 (8.39) and N1···HN1 (6.14 kcal mol(-1)) H-bonds that were established to be slightly anti-cooperative, leads to its transformation into the G*·G base mispair through a single transition state (|C6N1N1C6| = 37.1°; C1), namely to the interconversion into itself. It was shown that the G·G* ↔ G*·G tautomerisation via the DPT is assisted by the third specific contact, that sequentially switches along the intrinsic reaction coordinate (IRC) in an original way: (G)N2H···N2(G*) H-bond (-25.13 to -10.37) → N2···N2 van der Waals contact (-10.37 to -9.23) → (G)N2···HN2(G*) H-bond (-9.23 to 0.79) → (G*)N2···HN2(G) H-bond (0.79 to 7.35 Bohr). The DPT tautomerisation was found to proceed through the asynchronous concerted mechanism by employing the QM/QTAIM approach and the methodology of the scans of the geometric, electron-topological, energetic, polar and NBO properties along the IRC. Nine key points, that can be considered as part of the tautomerisation repertoire, have been established and analyzed in detail. Furthermore, it was shown that the G·G* or G*·G base mispair is a thermodynamically and dynamically stable structure with a lifetime of 8.22 × 10(-10) s and all 6 low-frequency intermolecular vibrations are able to develop during this time span. Lastly, our results highlight the importance of the G·G* ↔ G*·G DPT tautomerisation, which can have implications for biological and chemical sensing applications.

Does the tautomeric status of the adenine bases change upon the dissociation of the A*·A(syn) Topal-Fresco DNA mismatch? A combined QM and QTAIM atomistic insight.

We have scrupulously explored the tautomerisation mechanism via the double proton transfer of the A*·A(syn) Topal-Fresco base mispair (C(s) 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*·A(syn) ↔ A·A*(syn) tautomerisation is the asynchronous concerted process. It was established that the A*·A(syn) 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*·A(syn) 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*·A(syn) base mispair into the monomers during DNA replication.

Atomistic understanding of the C·T mismatched DNA base pair tautomerization via the DPT: QM and QTAIM computational approaches.

It was established that the cytosine·thymine (C·T) mismatched DNA base pair with cis-oriented N1H glycosidic bonds has propeller-like structure (|N3C4C4N3| = 38.4°), which is stabilized by three specific intermolecular interactions-two antiparallel N4H…O4 (5.19 kcal mol(-1)) and N3H…N3 (6.33 kcal mol(-1)) H-bonds and a van der Waals (vdW) contact O2…O2 (0.32 kcal mol(-1)). The C·T base mispair is thermodynamically stable structure (ΔG(int) = -1.54 kcal mol(-1) ) and even slightly more stable than the A·T Watson-Crick DNA base pair (ΔG(int) = -1.43 kcal mol(-1)) at the room temperature. It was shown that the C·T ↔ C*·T* tautomerization via the double proton transfer (DPT) is assisted by the O2…O2 vdW contact along the entire range of the intrinsic reaction coordinate (IRC). The positive value of the Grunenberg's compliance constants (31.186, 30.265, and 22.166 Å/mdyn for the C·T, C*·T*, and TS(C·T ↔ C*·T*), respectively) proves that the O2…O2 vdW contact is a stabilizing interaction. Based on the sweeps of the H-bond energies, it was found that the N4H…O4/O4H…N4, and N3H…N3 H-bonds in the C·T and C*·T* base pairs are anticooperative and weaken each other, whereas the middle N3H…N3 H-bond and the O2…O2 vdW contact are cooperative and mutually reinforce each other. It was found that the tautomerization of the C·T base mispair through the DPT is concerted and asynchronous reaction that proceeds via the TS(C·T ↔ C*·T*) stabilized by the loosened N4-H-O4 covalent bridge, N3H…N3 H-bond (9.67 kcal mol(-1) ) and O2…O2 vdW contact (0.41 kcal mol(-1) ). The nine key points, describing the evolution of the C·T ↔ C*·T* tautomerization via the DPT, were detected and completely investigated along the IRC. The C*·T* mispair was revealed to be the dynamically unstable structure with a lifetime 2.13·× 10(-13) s. In this case, as for the A·T Watson-Crick DNA base pair, activates the mechanism of the quantum protection of the C·T DNA base mispair from its spontaneous mutagenic tautomerization through the DPT.

Atomistic nature of the DPT tautomerisation of the biologically important C·C* DNA base mispair containing amino and imino tautomers of cytosine: a QM and QTAIM approach.

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 (TSC·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 TSC·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.

Atomistic mechanisms of the tautomerization of the G·C base pairs through the proton transfer: quantum-chemical survey.

This study is devoted to the investigation of the G·C*tO2(WC)↔G*NH3·C*t(WC), G·C*O2(WC)↔G*NH3·C*(WC) and G*·C*O2(WC)↔G*NH3·C(wWC)↓ tautomerization reactions occurring through the proton transfer, obtained at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in gas phase under normal conditions ('WC' means base pair in Watson-Crick configuration, T=298.15 K). These reactions lead to the formation of the G*NH3·C*t(WC), G*NH3·C*(WC) and G*NH3·C(wWC)↓ base pairs by the participation of the G*NH3 base with NH3 group. Gibbs free energies of activation for these reactions are 6.43, 11.00 and 1.63 kcal·mol-1, respectively. All of these tautomerization reactions are dipole active. Finally, we believe that these non-dissociative processes, which are tightly connected with the tautomeric transformations of the G·C base pairs, play an outstanding role in supporting of the spatial structure of the DNA and RNA molecules with various functional purposes.

Novel mechanisms of the conformational transformations of the biologically important G·C nucleobase pairs in Watson-Crick, Hoogsteen and wobble configurations via the mutual rotations of the bases around the intermolecular H-bonds: a QM/QTAIM study.

At the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of quantum-mechanical theory, we provide for the first time a comprehensive investigation of the physico-chemical mechanisms of the 55 conformational transformations of the biologically-important G·C nucleobase pairs - Watson-Crick (WC), reverse Watson-Crick (rWC), Hoogsteen (H), reverse Hoogsteen (rH), wobble (w) and reverse wobble (rw) base pairs by the participation of the G and C bases in the canonical and rare tautomeric forms ("r" - means reverse configuration of the base pair). It was established that all these G·C nucleobase pairs can conformationally transform into each other without the changing of the tautomeric status of the G and C bases. These transitions occur through significantly non-planar transition states via the mutual rotation of the G and C bases relative to each other within the G·C nucleobase pair around the upper, middle or lower intermolecular H-bonds: WC ↔ rWC, WC ↔ rwWC, rWC ↔ WC, rWC ↔ wWC, wWC ↔ rwWC, H ↔ rH, H ↔ rwH, rH ↔ H, rH ↔ wH, wH ↔ rwH. Gibbs free energies ΔG of activation for these conformational transformations are ΔG = 2.96-19.04/3.58-13.36 kcal mol-1 (in vacuum under normal conditions (T = 298.15 K)), which means that these reactions proceed quite fast. Obtained conformational transformations are accompanied by the disruption and further formation of the intermolecular specific contacts in the G·C nucleobase pairs (H-bonds and attractive van der Waals contacts). As a result, 76 conformers of the G·C nucleobase pairs were established - 48 base pairs in WC, rWC, wWC and rwWC configurations and 28 base pairs in H, rH, wH and rwH configurations with relative Gibbs free ΔG/electronic ΔE energies in the range ΔG/ΔE = 0.00-44.73/0.00-46.99 and ΔG/ΔE = 0.00-37.52/0.00-38.54 kcal mol-1, respectively (in vacuum under normal conditions). Experimental investigation and verification of the novel G·C nucleobase pairs are promising tasks for the future research. Based on the obtained data, biologically important conclusions were made about the importance of the conformational mobility of the G·C nucleobase pairs for the understanding of the functioning of the DNA and RNA molecules and their transition from the parallel into the anti-parallel duplexes and vice versa.

A new era of the prototropic tautomerism of the quercetin molecule: A QM/QTAIM computational advances.

In this study for the first time we have revealed and investigated in details 123 different prototropic tautomers of the most stable conformer of the quercetin molecule using quantum-mechanical calculations at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of QM theory. We have found that in the most energetically favorable prototropic tautomer mobile hydrogen atoms are localized at the О3, О3', О4', О5, and О7 exocyclic oxygen atoms. Molecular tautomers are in the range of the Gibbs free energies from 0.0 to 69.8 kcal·mol-1, while zwitterionic ones - from 30.1 до 172.8 kcal·mol-1 at normal conditions. It was also reliably established that the weakest point causing the decyclization of the molecule is its C ring - this reaction is launched by the transition of the proton from the C8H group to the endocyclic O1 oxygen atom. All prototropic tautomers, except two cases, are joined by the intramolecular cooperative specific interactions (from 1 to 5) - H-bonds and attractive van der Waals contacts, which have been revealed and characterized by QTAIM analysis. Communicated by Ramaswamy H. Sarma.

Conformational transitions of the quercetin molecule via the rotations of its rings: a comprehensive theoretical study.

Quercetin is an important flavonoid compound, usually extracted from plants, vegetables and fruits such as blueberries, apples, green tea, wine, onions and possessing broad range of pharmacological properties, in particular, powerful antioxidant, antitoxic, antiinflammation and antimicrobial effects due to its various reactive sites. The structure of this phenolic compound consists of three (A + C) and B rings, bearing five hydroxyl groups. Primarily, the chemical structure of quercetin determines its physico-chemical properties. Earlier, it was established that isolated quercetin molecule can acquire 48 stable conformations (24 planar and 24 non-planar) due to the mobility of its hydroxyl groups and (A + C) and B rings with relative Gibbs free energies in the range of 0.0-25.3 kcal·mol-1 under normal conditions (Brovarets' et al., 2019c). In this work by quantum-mechanical calculations at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory and Bader's 'Quantum Theory of Atoms in Molecules', we have theoretically modeled the interconversions in the 24 pairs of the conformers of the quercetin molecule, occuring via the rotation of its non-deformable (A+С) and B rings around the С2-С1' bond through the quasi-orthogonal transition state with low values of the imaginary frequencies (28-33/29-36 cm-1) and Gibbs free energies of activation in the range of 2.17-5.68/1.86-4.90 kcal·mol-1 in the continuum with dielectric permittivity ε = 1/ε = 4 under normal conditions. Also, we studied the changes of the number of physico-chemical characteristics of all intramolecular-specific contacts - hydrogen bonds and attractive van der Waals contacts during these conformational rearrangements.Communicated by Ramaswamy H. Sarma.

Conformational diversity of the quercetin molecule: a quantum-chemical view.

This paper focuses on the comprehensive conformational analysis of the quercetin molecule with a broad range of the therapeutic and biological actions. All possible conformers of these molecule, corresponding to the local minima on the potential energy hypersurface, have been obtained by the sequential rotation of its five hydroxyl groups and also by the rotation of its (A + C) and B rings relatively each other. Altogether, it was established 48 stable conformers, among which 24 conformers possess planar structure and 24 conformers - nonplanar structure. Their structural, symmetrical, energetical and polar characteristics have been investigated in details. Quantum-mechanical calculations indicate that conformers of the quercetin molecule are polar structures with a dipole moment, which varies within the range from 0.35 to 9.87 Debay for different conformers. Relative Gibbs free energies of these conformers are located within the range from 0.0 to 25.3 kcal·mol-1 in vacuum under normal conditions. Impact of the continuum with ε = 4 leads to the decreasing of the Gibbs free energies (-0.19-18.15 kcal·mol-1) and increasing of the dipole moment (0.57-12.48 D). It was shown that conformers of the quercetin molecule differ from each other by the intramolecular specific contacts (two or three), stabilizing all possible conformers of the molecule - H-bonds (both classical ОН…Ðž and so-called unusual С'Н…Ðž and ОН…Ð¡') and attractive van-der-Waals contacts О…Ðž. Obtained conformational analysis for the quercetin molecule enables to provide deeper understanding of the 'structure-function' relationship and also to suggest its mechanisms of the therapeutic and biological actions.Communicated by Ramaswamy H. Sarma.

A Quantum-Mechanical Looking Behind the Scene of the Classic G·C Nucleobase Pairs Tautomerization.

For the first time, at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory, a comprehensive quantum-mechanical investigation of the physico-chemical mechanism of the tautomeric wobblization of the four biologically-important G·C nucleobase pairs by the participation of the monomers in rare, in particular mutagenic, tautomeric forms (marked with an asterisk) was provided. These novel tautomeric transformations (wobblization or shifting of the bases within the pair) are intrinsically inherent properties of the G·C nucleobase pairs. In this study, we have obtained intriguing results, lying far beyond the existing representations. Thus, it was shown that Löwdin's G*·C*(WC) base pair does not tautomerize according to the wobblization mechanism. Tautomeric wobblization of the G*·C*(rWC) (relative Gibbs free energy ΔG = 0.00/relative electronic energy ΔE = 0.00 kcal·mol-1) ("r"-means the configuration of the base pair in reverse position; "WC"-the classic Watson-Crick configuration) and G*t·C*(H) (ΔG = -0.19/ΔE = 0.29 kcal·mol-1) ("H"-Hoogsteen configuration;"t" denotes the O6H hydroxyl group in the trans position) base pairs are preceded by the stages of the base pairs tautomerization by the single proton transfer (SPT). It was established that the G*t·C*(rH) (ΔG = 2.21/ΔE = 2.81 kcal·mol-1) base pair can be wobbled through two different pathways via the traditional one-stage mechanism through the TSs, which are tight G+·C- ion pairs, stabilized by the participation of only two intermolecular H-bonds. It was found out that the G·C base pair is most likely incorporated into the DNA/RNA double helix with parallel strands in the G*·C*(rWC), G·C*(rwwc), and G*·C(rwwc) ("w"-wobble configuration of the pair) tautomeric forms, which are in rapid tautomeric equilibrium with each other. It was proven that the G*·C*(rWC) nucleobase pair is also in rapid tautomeric equilibrium with the eight tautomeric forms of the so-called Levitt base pair. It was revealed that a few cases of tautomerization via the DPT of the nucleobase pairs by the participation of the C8H group of the guanine had occurred. The biological role of the obtained results was also made apparent.

Intramolecular tautomerization of the quercetin molecule due to the proton transfer: QM computational study.

Quercetin molecule (3, 3', 4', 5, 7-pentahydroxyflavone, C15H10O7) is an important flavonoid compound of natural origin, consisting of two aromatic A and B rings linked through the C ring with endocyclic oxygen atom and five hydroxyl groups attached to the 3, 3', 4', 5 and 7 positions. This molecule is found in many foods and plants, and is known to have a wide range of therapeutic properties, like an anti-oxidant, anti-toxic, anti-inflammatory etc. In this study for the first time we have revealed and investigated the pathways of the tautomeric transformations for the most stable conformers of the isolated quercetin molecule (Brovarets' & Hovorun, 2019) via the intramolecular proton transfer. Energetic, structural, dynamical and polar characteristics of these transitions, in particular relative Gibbs free and electronic energies, characteristics of the intramolecular specific interactions-H-bonds and attractive van der Waals contacts, have been analysed in details. It was demonstrated that the most probable process among all investigated is the proton transfer from the O3H hydroxyl group of the C ring to the C2' carbon atom of the C2'H group of the B ring along the intramolecular O3H…C2' H-bond with the further formation of the C2'H2 group. It was established that the proton transfer from the hydroxyl groups to the carbon atoms of the neighboring CH groups is assisted at the transition states by the strong intramolecular HCH…O H-bond (~28.5 kcal∙mol-1). The least probable path of the proton transfer-from the C8H group to the endocyclic O1 oxygen atom-causes the decyclization of the C ring in some cases. It is shortly discussed the biological importance of the obtained results.

Atomistic mechanisms of the double proton transfer in the H-bonded nucleobase pairs: QM/QTAIM computational lessons.

In this Review, we have summarized and generalized the results of the investigation of the microstructural mechanisms of the tautomerization by the counter movement of the protons along the neighboring intermolecular H-bonds in 22 biologically important pairs of nucleotide bases in the framework of the original method, which allows to trace the evolution of the physicochemical parameters, that characterize these processes along the intrinsic reaction coordinate (IRC). It was demonstrated the performance of the introduction of the conception of the key points (KPs) (from nine to five, depending on the symmetry and nature of system), which exhaustively characterize the flow of the tautomerization processes. It was proved that for all tautomerizing base pairs the extrema of the first derivative of the electron energy of the complex by IRC coincide with the second and penultimate KPs, in which the Laplacian of the electron density equals zero at the corresponding (3,-1) bond critical points of the H-bonds. It was established the linear dependence of the width of the transition state zone of the DPT tautomerization on the degree of its asynchrony. Authors emphasize that the tautomerization reaction through the DPT of the H-bonded pairs of nucleotide bases can be considered successful in those and only in those case if the tautomerized complex is a dynamically stable system, during lifetime of which low-frequency intermolecular vibrations could develop. Perspectives of the application of the obtained approaches to the thorough study of the proton transfer processes in the biologically important objects have been briefly discussed.

Key microstructural mechanisms of the 2-aminopurine mutagenicity: Results of extensive quantum-chemical research.

As of today, a great amount of experimental and theoretical phenomenological data have been collected in the literature according the mutagenic action of the classical mutagen - 2-aminopurine (2AP). However, so far they have not received proper explanation and substantiation. In this Opinion Piece, we provide an overview of recent progress in computational design and modeling of the physico-chemical mechanisms of the mutagenic action of 2AP. Results of quantum-chemical studies, aimed at the elucidation of the key microstructural mechanisms of the mutagenicity of 2AP, have been summarized here. In this context, for the first time it was outlined the most important surveys: Why 2AP is incorporated into DNA in trace concentrations? Whether classical mechanisms presented in the literature according the formation of the rare tautomers of canonical DNA bases work also for base analogue - 2AP? In what way 2AP induces replication and incorporation errors? Whether the amino-imino tautomerisation of 2AP is related to its mutagenicity, that is whether the 2AP* rare tautomer is mutagenic? It is emphasized that the applied approach has a proper theoretical substantiation, since it is based on our microstructural theory of the spontaneous point mutagenesis in DNA, and at the same time it accumulates scenarios of the origin of the induced point errors - transitions and transversions, which the classical Watson-Crick tautomeric hypothesis permits. Moreover, using author's methodology, the profiles of the main physico-chemical characteristics for the tautomerisation reactions involving 2AP, which are integral parts of the biologically important tautomerically-conformational transformations, have been presented. Obtained results open new perspectives for prediction and design of the mutagenic derivatives of the nucleotide bases of any structure and origin before their synthesis and also for planning of new experiments and interpretation of the existing data. Abbreviations 2AP 2-Aminopurine A adenine C cytosine DPT double proton transfer G guanine IRC intrinsic reaction coordinate KP key point T thymine w wobble WC Watson-Crick vdW van der Waals H-bond hydrogen bond Communicated by Ramaswamy H. Sarma.

Novel Tautomerisation Mechanisms of the Biologically Important Conformers of the Reverse Löwdin, Hoogsteen, and Reverse Hoogsteen G*·C* DNA Base Pairs via Proton Transfer: A Quantum-Mechanical Survey.

For the first time, in this study with the use of QM/QTAIM methods we have exhaustively investigated the tautomerization of the biologically-important conformers of the G*·C* DNA base pair-reverse Löwdin G*·C*(rWC), Hoogsteen G*'·C*(H), and reverse Hoogsteen G*'·C*(rH) DNA base pairs-via the single (SPT) or double (DPT) proton transfer along the neighboring intermolecular H-bonds. These tautomeric reactions finally lead to the formation of the novel G· C O 2 * (rWC), G N 2 * · C(rWC), G*'N2·C(rWC), G N 7 * · C(H), and G*'N7·C(rH) DNA base mispairs. Gibbs free energies of activation for these reactions are within the range 3.64-31.65 kcal·mol-1 in vacuum under normal conditions. All TSs are planar structures (Cs symmetry) with a single exception-the essentially non-planar transition state TSG*·C*(rWC)↔G+·C-(rWC) (C1 symmetry). Analysis of the kinetic parameters of the considered tautomerization reactions indicates that in reality only the reverse Hoogsteen G*'·C*(rH) base pair undergoes tautomerization. However, the population of its tautomerised state G*'N7·C(rH) amounts to an insignificant value-2.3·10-17. So, the G*·C*(rWC), G*'·C*(H), and G*'·C*(rH) base pairs possess a permanent tautomeric status, which does not depend on proton mobility along the neighboring H-bonds. The investigated tautomerization processes were analyzed in details by applying the author's unique methodology-sweeps of the main physical and chemical parameters along the intrinsic reaction coordinate (IRC). In general, the obtained data demonstrate the tautomeric mobility and diversity of the G*·C* DNA base pair.

Surprising Conformers of the Biologically Important A·T DNA Base Pairs: QM/QTAIM Proofs.

For the first time novel high-energy conformers-A·T(wWC) (5.36), A·T(wrWC) (5.97), A·T(wH) (5.78), and A·T(wrH) (ΔG = 5.82 kcal·mol-1) (See Graphical Abstract) were revealed for each of the four biologically important A·T DNA base pairs - Watson-Crick A·T(WC), reverse Watson-Crick A·T(rWC), Hoogsteen A·T(H) and reverse Hoogsteen A·T(rH) at the MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level of quantum-mechanical theory in the continuum with ε = 4 under normal conditions. Each of these conformers possesses substantially non-planar wobble (w) structure and is stabilized by the participation of the two anti-parallel N6H/N6H'…O4/O2 and N3H…N6 H-bonds, involving the pyramidalized amino group of the A DNA base as an acceptor and a donor of the H-bonding. The transition states - TSA·T(WC)↔A·T(wWC), TSA·T(rWC)↔A·T(wrWC), TSA·T(H)↔A·T(wH), and TSA·T(rH)↔A·T(wrH), controlling the dipole-active transformations of the conformers from the main plane-symmetric state into the high-energy, significantly non-planar state and vice versa, were localized. They also possess wobble structures similarly to the high-energy conformers and are stabilized by the participation of the N6H/N6H'…O4/O2 and N3H…N6 H-bonds. Discovered conformers of the A·T DNA base pairs are dynamically stable short-lived structures [lifetime τ = (1.4-3.9) ps]. Their possible biological significance and future perspectives have been briefly discussed.