ΔEint – the counterpoise-corrected electronic energy of interaction; ΔΔE – the reverse barrier (difference in electronic energy) of tautomerisation; ΔΔG – the reverse barrier (difference in Gibbs free energy) of tautomerisation

Table 5. Electronic and Gibbs free energies (in kcal/mol) (T= 298.15 K) of complexes of DNA bases with water molecule obtained at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in vacuum#

#### **4.5 Tautomerisation of the DNA bases in dimers**

Theoretical and experimental studies also explored agents other than water, which can enhance the stability of rare tautomers of DNA bases in the gas phase. Of particular interest were their interactions with amino acids (Fan et al., 2010; Samijlenko et al., 2001, 2004;

Elementary Molecular Mechanisms of the Spontaneous Point

the electronic and geometrical complementarity.

this leads to a spontaneous Ade·Thy→Gua·Cyt transition.

same characteristics obtained for the natural Watson-Crick base pairs.

**5. Mispairs involving mutagenic tautomers of DNA bases** 

enol tautomer can appear.

incorporation.

Mutations in DNA: A Novel Quantum-Chemical Insight into the Classical Understanding 79

compound 4(3H)-pyrimidinone dimer using *ab initio* MO calculations and liquid-phase IR spectroscopy. The calculations suggest that the DPT processes in these dimers are energetically accessible and temperature-dependent IR measurements of the model compound reveal that slight thermal energy can induce the DPT reaction, and hence the

The mutagenic tautomers of DNA bases can form six possible purine-pyrimidine base pairs - Ade·Cyt\*, Ade\*Cyt, Gua\*Thy, GuaThy\*, Ade\*Thy\* and Gua\*Cyt\* - thereby demonstrating

In a DNA double helix, Gua forms an H-bonded pair with Cyt. Meanwhile, the mutagenic enol form of Gua (Gua\*) can pair with Thy (Brovarets' & Hovorun, 2010d; Danilov et al., 2005; Mejía-Mazariegos & Hernández-Trujillo, 2009) instead of Cyt. Similarly, the mutagenic imino form of Cyt (Cyt\*) pairs with Ade (Danilov et al., 2005; Fonseca Guerra et al., 2006) instead of Gua. Then, during replication, when the two strands separate the Thy and Ade bases of the anomalous Gua\*·Thy and Ade·Cyt\* base pairs would combine with Ade and Thy instead of Cyt and Gua, respectively. Thus, the scheme postulated in (Watson & Crick, 1953a, 1953b) leads to a spontaneous transition Gua·Cyt→Ade·Thy in the subsequent rounds of replication if not repaired appropriately (Kunz et al., 2009). In DNA, the canonical form of Ade combines with the canonical form of Thy; however, the Ade\* mutagenic imino tautomer combines with Cyt rather than with Thy, while the mutagenic enol form of Thy\* forms a pair with Gua instead of Ade. After the strand separation, the counter-base pairs Gua·Cyt and Cyt·Gua instead of Ade·Thy and Thy·Ade are formed, respectively. As a result

To gain more insight into the nature of the formed tautomeric base pairs, we have analysed their hydrogen-bonding mechanism and geometrical features to compare them with the

As shown by Kool et al. in the experiments on DNA replication (Guckian et al., 2000; Kool et al., 2000; Morales & Kool, 2000; Kool, 2002), an incoming nucleotide must be able to form, with its partner in the template, a base pair which sterically resembles the natural Watson-Crick base pair(Ade·Thy or Gua·Cyt). In addition, it was recently shown that the ability of the incoming base to form H-bonds with the template base is also of great importance (Bebenek et al., 2011; W. Wang et al., 2011). Bebenek et al. (Bebenek et al., 2011) have shown that a human DNA polymerase λ poised to misinsert dGTP opposite a template Thy can form a mismatch with Watson–Crick-like geometry and Wang et al. (W. Wang et al., 2011) observed that the Ade·Cyt mismatch can mimic the shape of cognate base pairs at the site of

According to the geometric selection mechanism of bases as a principal determinant of DNA replication fidelity (Echols & Goodman, 1991; Goodman, 1997; Sloane et al., 1988), the geometrical and electrostatic properties of the polymerase active site are likely to have a profound influence on nucleotide-insertion specificities. This influence would strongly favor the insertion of the base pairs having an optimal geometry, in which the distance between C1 atoms of paired nucleotides and the N9–C1(Pur)–C1(Pyr) and N1–C1(Pyr)–C1(Pur) angles characterizing the nucleotide pair in double helix are most closely approximated to

Stepanyugin et al., 2002a, 2002b) and protons or alkali metal cations (Lippert et al., 1986; Lippert & Gupta, 2009; Samijlenko et al., 2010; Šponer et al., 2001), as the extra positive charge could stabilize the structure of rare tautomers through an intramolecular salt bridge. Moreover, the coordination of metal ions to nucleobases is known to lead frequently to the stabilization of rare tautomeric forms (Burda et al., 2000; Lippert et al., 1986; Lippert & Gupta, 2009; Samijlenko et al., 2010), with numerous examples reported for various nucleobases (Lippert & Gupta, 2009; Lippert et al., 1986; Schoellhorn et al., 1989; Renn et al., 1991; Zamora et al., 1997). In these metal-stabilized rare tautomers, the metal is located at a position that is usually occupied by a proton, forcing the proton to move to another position and thereby generating the rare tautomer.

Yang and Rodgers (Yang & Rodgers, 2004) were probably the first to bring up the important question that a possible way of tautomerisation may be through dimerization.

In the literature, there are available papers devoted to the investigation of the tautomerisation of DNA bases by the different chemical compounds, e.g. glycine-assisted tautomerisation of Ura (Da̧bkowska et al., 2005) and tautomerisation of Thy by methanol (Fan et al., 2010). However, it was established that such interactions result in the reducing of the internal barrier of tautomerisation and thermodynamic equilibrium could be easily attained at room temperature, the dynamical stability of the tautomerized in such a way complexes remained out of authors' eyeshot.

Providing *ab initio* quantum-chemical study of hydrogen-bonded complexes of acetic acid with canonical and mutagenic tautomers of DNA bases methylated at the glycosidic nitrogen atoms *in vacuo* and continuum with a low dielectric constant we established that all tautomerized complexes are dynamically unstable because their electronic energy barriers for the reverse tautomerisation reaction do not exceed zero-point energy of corresponding vibrational modes, frequencies of which become imaginary in the transition states of tautomerisation (Brovarets' et al., 2010c; Brovarets' et al., 2012) (Fig. 5).

A potential pathway for the generation of the mutagenic amino-enol form of guanine is reported by Padermshoke et al. (Padermshoke et al., 2008), who investigated DPT reactions in three guanine-guanine dimers, a guanine-thymine wobble base pair, and a model

## **5. Mispairs involving mutagenic tautomers of DNA bases**

enol tautomer can appear.

78 Quantum Chemistry – Molecules for Innovations

Stepanyugin et al., 2002a, 2002b) and protons or alkali metal cations (Lippert et al., 1986; Lippert & Gupta, 2009; Samijlenko et al., 2010; Šponer et al., 2001), as the extra positive charge could stabilize the structure of rare tautomers through an intramolecular salt bridge. Moreover, the coordination of metal ions to nucleobases is known to lead frequently to the stabilization of rare tautomeric forms (Burda et al., 2000; Lippert et al., 1986; Lippert & Gupta, 2009; Samijlenko et al., 2010), with numerous examples reported for various nucleobases (Lippert & Gupta, 2009; Lippert et al., 1986; Schoellhorn et al., 1989; Renn et al., 1991; Zamora et al., 1997). In these metal-stabilized rare tautomers, the metal is located at a position that is usually occupied by a proton, forcing the proton to move to another position

Yang and Rodgers (Yang & Rodgers, 2004) were probably the first to bring up the important

In the literature, there are available papers devoted to the investigation of the tautomerisation of DNA bases by the different chemical compounds, e.g. glycine-assisted tautomerisation of Ura (Da̧bkowska et al., 2005) and tautomerisation of Thy by methanol (Fan et al., 2010). However, it was established that such interactions result in the reducing of the internal barrier of tautomerisation and thermodynamic equilibrium could be easily attained at room temperature, the dynamical stability of the tautomerized in such a way

Providing *ab initio* quantum-chemical study of hydrogen-bonded complexes of acetic acid with canonical and mutagenic tautomers of DNA bases methylated at the glycosidic nitrogen atoms *in vacuo* and continuum with a low dielectric constant we established that all tautomerized complexes are dynamically unstable because their electronic energy barriers for the reverse tautomerisation reaction do not exceed zero-point energy of corresponding vibrational modes, frequencies of which become imaginary in the transition states of

Fig. 5. Qualitative representation of potential energy profile of the X↔X\* conversion. X and X\* – complexes containing DNA base in canonical and mutagenic tautomeric forms,

A potential pathway for the generation of the mutagenic amino-enol form of guanine is reported by Padermshoke et al. (Padermshoke et al., 2008), who investigated DPT reactions in three guanine-guanine dimers, a guanine-thymine wobble base pair, and a model

question that a possible way of tautomerisation may be through dimerization.

tautomerisation (Brovarets' et al., 2010c; Brovarets' et al., 2012) (Fig. 5).

and thereby generating the rare tautomer.

complexes remained out of authors' eyeshot.

respectively

The mutagenic tautomers of DNA bases can form six possible purine-pyrimidine base pairs - Ade·Cyt\*, Ade\*Cyt, Gua\*Thy, GuaThy\*, Ade\*Thy\* and Gua\*Cyt\* - thereby demonstrating the electronic and geometrical complementarity.

In a DNA double helix, Gua forms an H-bonded pair with Cyt. Meanwhile, the mutagenic enol form of Gua (Gua\*) can pair with Thy (Brovarets' & Hovorun, 2010d; Danilov et al., 2005; Mejía-Mazariegos & Hernández-Trujillo, 2009) instead of Cyt. Similarly, the mutagenic imino form of Cyt (Cyt\*) pairs with Ade (Danilov et al., 2005; Fonseca Guerra et al., 2006) instead of Gua. Then, during replication, when the two strands separate the Thy and Ade bases of the anomalous Gua\*·Thy and Ade·Cyt\* base pairs would combine with Ade and Thy instead of Cyt and Gua, respectively. Thus, the scheme postulated in (Watson & Crick, 1953a, 1953b) leads to a spontaneous transition Gua·Cyt→Ade·Thy in the subsequent rounds of replication if not repaired appropriately (Kunz et al., 2009). In DNA, the canonical form of Ade combines with the canonical form of Thy; however, the Ade\* mutagenic imino tautomer combines with Cyt rather than with Thy, while the mutagenic enol form of Thy\* forms a pair with Gua instead of Ade. After the strand separation, the counter-base pairs Gua·Cyt and Cyt·Gua instead of Ade·Thy and Thy·Ade are formed, respectively. As a result this leads to a spontaneous Ade·Thy→Gua·Cyt transition.

To gain more insight into the nature of the formed tautomeric base pairs, we have analysed their hydrogen-bonding mechanism and geometrical features to compare them with the same characteristics obtained for the natural Watson-Crick base pairs.

As shown by Kool et al. in the experiments on DNA replication (Guckian et al., 2000; Kool et al., 2000; Morales & Kool, 2000; Kool, 2002), an incoming nucleotide must be able to form, with its partner in the template, a base pair which sterically resembles the natural Watson-Crick base pair(Ade·Thy or Gua·Cyt). In addition, it was recently shown that the ability of the incoming base to form H-bonds with the template base is also of great importance (Bebenek et al., 2011; W. Wang et al., 2011). Bebenek et al. (Bebenek et al., 2011) have shown that a human DNA polymerase λ poised to misinsert dGTP opposite a template Thy can form a mismatch with Watson–Crick-like geometry and Wang et al. (W. Wang et al., 2011) observed that the Ade·Cyt mismatch can mimic the shape of cognate base pairs at the site of incorporation.

According to the geometric selection mechanism of bases as a principal determinant of DNA replication fidelity (Echols & Goodman, 1991; Goodman, 1997; Sloane et al., 1988), the geometrical and electrostatic properties of the polymerase active site are likely to have a profound influence on nucleotide-insertion specificities. This influence would strongly favor the insertion of the base pairs having an optimal geometry, in which the distance between C1 atoms of paired nucleotides and the N9–C1(Pur)–C1(Pyr) and N1–C1(Pyr)–C1(Pur) angles characterizing the nucleotide pair in double helix are most closely approximated to

Elementary Molecular Mechanisms of the Spontaneous Point
