**Abstract**

This Chapter summarizes recent quantum-chemical (QM) investigations of the novel conformational and tautomeric states on the potential energy hypersurface of the classical AT/AU nucleobase pairs. For the first time, it was observed 28 local minima for each base pair excluding enantiomers - planar, non-planar base pairs and structures with wobble geometry. Considered excited conformationallytautomeric states of the classical AT DNA base pair have been revealed in the Nucleic Acid Database by structural bioinformatics. These data shed light on the biological significance of the unusual AT/AU nucleobase pairs for the functioning of the nucleic acids at the quantum level.

**Keywords:** quantum biology, AT and AU nucleobase pairs, tautomeric state, conformational state, wobble geometry, quantum-chemical calculation, structural bioinformatics

#### **1. Introduction**

Since the discovery of the spatial organization of the DNA molecule by James Watson & Francis Crick [1, 2], it is traditionally believed that canonical Watson-Crick AT and GC DNA base pairs are quite conservative structures. These classical DNA base pairs almost do not have tautomeric variability and essential conformational mobility at the dynamical behavior of DNA molecule [2]. Generally, it is suggested that bases in the *anti*-conformation able to form a pair according to the so-called Watson-Crick (WC) scheme joined through the three intermolecular hydrogen (H) bonds [3]. At the same time, many biologists-contemporaries questioned the proposed Watson-Crick conformation, since X-ray resolution does not allow to establish for sure the precise conformation of the base pairs constituting to the DNA double helix. Exactly by this reason Maurice Wilkins – the third author of the discovery of the DNA structure – explained the reason why Rosalind Franklin doubted in modeling the structure of DNA [4]. And even forefathers of the discovery noted that suggested by them structure "must be regarded as unproved until it has been checked against more exact results" [1]. Also, Linus Pauling opposed Watson-Crick model of the paring of the bases "because of existing uncertainty about the detailed structure of nucleic acid" (personal correspondence to the Nobel Committee for Chemistry and Physics).

of the lone electron pair of nitrogen amino atom with π-electron system of the ring [54–56]. This data enables us to suggest the potential energy surface of the classical А�Т base pairs and also to predict pathways of their interconversions. Moreover, this modeling could be used for the understanding and description in details of the physico-chemical mechanisms of the DNA functioning, in particular DNA "breath-

*Where Quantum Biochemistry Meets Structural Bioinformatics: Excited Conformationally…*

Also, obtained data would enable to make new insights into the understanding the DNA and RNA structural biology, which are based on their conformational and tautomeric variety. By the methods of structural bioinformatics it was

revealed unusual conformationally-tautomeric states of the A�T DNA base pair in the Nucleic Acid Database, confirming their existence in biological systems. Altogether, further this could be extended to the area of epigenetics and

Equilibrium geometries of the investigated DNA base pairs, as well as their harmonic vibrational frequencies have been calculated at the B3LYP/6–311++G(d, p) level of theory [54–58], using Gaussian'09 package [59]. Applied level of theory has proved itself successful for the calculations of the similar systems [60–62]. A scaling factor that is equal to 0.9668 has been applied in the present work for the

All calculations have been carried out in the continuum with ε = 1, that adequately reflects the processes occurring in real biological systems without deprivation of the structurally functional properties of the bases in the composition of DNA, and in the continuum with ε = 4, which satisfactorily models the substantially hydrophobic recognition pocket of the DNA-polymerase machinery as a part of the

Single point energy calculations have been performed at the MP2/6–311++(2df,

The Gibbs free energy G for all structures was obtained in the following way:

Electronic interaction energies ΔEint have been calculated at the MP2/6–311++G (2df,pd) level of theory as the difference between the total energy of the base pair and energies of the monomers and corrected for the basis set superposition error

Bader's quantum theory of Atoms in Molecules (QTAIM) [77–82], using program package AIMAll [77], was applied to analyze the electron density distribution. The presence of the bond critical point (BCP), namely the so-called (3,-1) BCP, and a bond path between hydrogen donor and acceptor, as well as the positive value of the Laplacian at this BCP (Δρ > 0), were considered as criteria for the H-bond formation [77–82]. Wave functions were obtained at the level of QM theory used

The atomic numbering scheme for the DNA bases is conventional [3]. In this study mutagenic or rare tautomeric forms are denoted by the asterisk [83–92].

G ¼ Eel þ Ecorr, (1)

correction of the harmonic frequencies of all complexes [63, 64].

where Eel – electronic energy, while Ecorr – thermal correction.

(BSSE) [73, 74] through the counterpoise procedure [75, 76].

ing", which has significant biological role [27, 28].

*DOI: http://dx.doi.org/10.5772/intechopen.94565*

experimental verification.

**2.1 Computational methods**

**2. Methods**

replisome [65–70].

pd) level of theory [71, 72].

for geometry optimization.

**5**

After some time, in 1959 Karst Hoogsteen fixed in crystal state a novel structure for the 1-methylthymine. 9-methyladenine base pair [5], which was named afterwards with the same name – Hoogsteen base pair, in which A purine base adopts the *syn*-conformation formed by flipping of its orientation on 180 degree according the T DNA base. Moreover, the distance between the glycosidic atoms C10 –C1<sup>0</sup> is shorter for Hoogsteen base pair in comparison with the classical WC base pair.

Altogether, the А�Т DNA base pair can acquire four biologically significant classical configurations – Watson-Crick А�Т(WC), reverse Watson-Crick А�Т(rWC), Hoogsteen А�Т(Н) and reverse Hoogsteen А�Т(rН) [5–26], due to the rotation of one of the bases in the Watson-Crick А�Т(WC) base pair according to the other on 180° around:


Discussed DNA base pairs are not static structures in the composition of DNA [27, 28]. Thus, the spontaneous A�T(WC)\$A�T(Н) conformational transition has been experimentally registered by the NMR spectroscopy on the DNA regions enriched by the classical A�T nucleobase pairs [22]. Despite numerous theoretical investigations, microstructural nature of these transitions still remains incomprehensible [20, 29].

Recently, in the literature especial attention has been paid to the searching and careful investigation of the novel conformational and tautomeric states of the classical A�T base pair [30–36], since it can expand their functionality. Generally saying, the topic of the prototropic tautomerism has attracted especial attention, in particular in the area of drug design [37], in physics of crystals [38], in the various created databases [39–41], multinuclear magnetic resonance [42], in NMR spectroscopy [43] as well as biologically important molecules [44–46].

This Chapter summarizes previous investigations, in particular performed by quantum-mechanical (QM) modeling [47–53]. Thus, it was established that the planar classical Watson-Crick А�Т DNA base pairs – Watson-Crick А�Т(WC), reverse Watson-Crick А�Т(rWC), Hoogsteen А�Т(Н) and reverse Hoogsteen А�Т(rН) structures possess unique ability to perform conformationally-tautomeric transitions [47–53]. It occurs *via* the non-planar transition states, *through* the structural or conformational rearrangements and intramolecular proton transfer along the intermolecular H-bonds.

These novel excited conformational and tautomeric states occur due to the quantum effects, e.g. amino group pyramidalization because of electron conjugation *Where Quantum Biochemistry Meets Structural Bioinformatics: Excited Conformationally… DOI: http://dx.doi.org/10.5772/intechopen.94565*

of the lone electron pair of nitrogen amino atom with π-electron system of the ring [54–56]. This data enables us to suggest the potential energy surface of the classical А�Т base pairs and also to predict pathways of their interconversions. Moreover, this modeling could be used for the understanding and description in details of the physico-chemical mechanisms of the DNA functioning, in particular DNA "breathing", which has significant biological role [27, 28].

Also, obtained data would enable to make new insights into the understanding the DNA and RNA structural biology, which are based on their conformational and tautomeric variety. By the methods of structural bioinformatics it was revealed unusual conformationally-tautomeric states of the A�T DNA base pair in the Nucleic Acid Database, confirming their existence in biological systems. Altogether, further this could be extended to the area of epigenetics and experimental verification.

#### **2. Methods**

discovery noted that suggested by them structure "must be regarded as unproved until it has been checked against more exact results" [1]. Also, Linus Pauling opposed Watson-Crick model of the paring of the bases "because of existing uncertainty about the detailed structure of nucleic acid" (personal correspondence to the

After some time, in 1959 Karst Hoogsteen fixed in crystal state a novel structure for the 1-methylthymine. 9-methyladenine base pair [5], which was named afterwards with the same name – Hoogsteen base pair, in which A purine base adopts the *syn*-conformation formed by flipping of its orientation on 180 degree according the

–C1<sup>0</sup> is shorter

T DNA base. Moreover, the distance between the glycosidic atoms C10

for Hoogsteen base pair in comparison with the classical WC base pair.

classical configurations – Watson-Crick А�Т(WC), reverse Watson-Crick

• the (A)C9-N9 axis from the *anti-* to *syn-*conformation, representing Hoogsteen A�T(H) base pair [5] involved into a number of biologically important processes such as recognition, damage induction and replication

• the (A)N7–N3(T) axis in the Hoogsteen base pair forming the reverse Hoogsteen A�T(rH) or so-called Haschemeyer–Sobell base pair [23–26].

Discussed DNA base pairs are not static structures in the composition of DNA [27, 28]. Thus, the spontaneous A�T(WC)\$A�T(Н) conformational transition has been experimentally registered by the NMR spectroscopy on the DNA regions enriched by the classical A�T nucleobase pairs [22]. Despite numerous theoretical investigations, microstructural nature of these transitions still remains incompre-

Recently, in the literature especial attention has been paid to the searching and careful investigation of the novel conformational and tautomeric states of the classical A�T base pair [30–36], since it can expand their functionality. Generally saying, the topic of the prototropic tautomerism has attracted especial attention, in particular in the area of drug design [37], in physics of crystals [38], in the various created databases [39–41], multinuclear magnetic resonance [42], in NMR spec-

This Chapter summarizes previous investigations, in particular performed by quantum-mechanical (QM) modeling [47–53]. Thus, it was established that the planar classical Watson-Crick А�Т DNA base pairs – Watson-Crick А�Т(WC), reverse Watson-Crick А�Т(rWC), Hoogsteen А�Т(Н) and reverse Hoogsteen А�Т(rН) structures possess unique ability to perform conformationally-tautomeric transitions [47–53]. It occurs *via* the non-planar transition states, *through* the structural or conformational rearrangements and intramolecular proton transfer along

These novel excited conformational and tautomeric states occur due to the quantum effects, e.g. amino group pyramidalization because of electron conjugation

troscopy [43] as well as biologically important molecules [44–46].

Altogether, the А�Т DNA base pair can acquire four biologically significant

А�Т(rWC), Hoogsteen А�Т(Н) and reverse Hoogsteen А�Т(rН) [5–26], due to the rotation of one of the bases in the Watson-Crick А�Т(WC) base pair according to

• the (A)N1–N3(T) axis, leading to the formation of the reverse Watson-Crick А�Т(rWC) or so-called Donohue DNA base pair [6], registered in the bioactive

Nobel Committee for Chemistry and Physics).

*DNA - Damages and Repair Mechanisms*

the other on 180° around:

[11–22];

hensible [20, 29].

the intermolecular H-bonds.

**4**

parallel-stranded DNA [7–12];

#### **2.1 Computational methods**

Equilibrium geometries of the investigated DNA base pairs, as well as their harmonic vibrational frequencies have been calculated at the B3LYP/6–311++G(d, p) level of theory [54–58], using Gaussian'09 package [59]. Applied level of theory has proved itself successful for the calculations of the similar systems [60–62]. A scaling factor that is equal to 0.9668 has been applied in the present work for the correction of the harmonic frequencies of all complexes [63, 64].

All calculations have been carried out in the continuum with ε = 1, that adequately reflects the processes occurring in real biological systems without deprivation of the structurally functional properties of the bases in the composition of DNA, and in the continuum with ε = 4, which satisfactorily models the substantially hydrophobic recognition pocket of the DNA-polymerase machinery as a part of the replisome [65–70].

Single point energy calculations have been performed at the MP2/6–311++(2df, pd) level of theory [71, 72].

The Gibbs free energy G for all structures was obtained in the following way:

$$\mathbf{G} = \mathbf{E}\_{\mathrm{el}} + \mathbf{E}\_{\mathrm{corr}},\tag{1}$$

where Eel – electronic energy, while Ecorr – thermal correction.

Electronic interaction energies ΔEint have been calculated at the MP2/6–311++G (2df,pd) level of theory as the difference between the total energy of the base pair and energies of the monomers and corrected for the basis set superposition error (BSSE) [73, 74] through the counterpoise procedure [75, 76].

Bader's quantum theory of Atoms in Molecules (QTAIM) [77–82], using program package AIMAll [77], was applied to analyze the electron density distribution. The presence of the bond critical point (BCP), namely the so-called (3,-1) BCP, and a bond path between hydrogen donor and acceptor, as well as the positive value of the Laplacian at this BCP (Δρ > 0), were considered as criteria for the H-bond formation [77–82]. Wave functions were obtained at the level of QM theory used for geometry optimization.

The atomic numbering scheme for the DNA bases is conventional [3]. In this study mutagenic or rare tautomeric forms are denoted by the asterisk [83–92].
