Tautomerism and protonation of guanine and cytosine in the gas phase and in aqueous solution have been examined by theoretical methods. High level ab initio calculations with inclusion of correlation effects at the Moller−Plesset level have been used to study these processes in the gas phase. The influence of solvent has been examined using self-consistent reaction field and Monte Carlo free energy perturbation simulations. The results provide a complete and accurate picture of tautomerism and protonation of these nucleic acid bases. Comparison with the available experimental data gives confidence in the quality of the results derived from theoretical computations. Inspection of the most stable tautomeric forms for the neutral and protonated nucleic acid bases allows rationalization of the formation of unusual DNA structures like the triple helix.

Tautomerism and protonation of guanine and cytosine. implications in the formation of hydrogen-bonded complexes

The energetic provisions for Lowdin's DNA mutational mechanism (Lowdin, P. O. Rev. Mod. Phys. 1963, 35, 724) of the formation of substitution DNA mutations were investigated for the guanine·cytosine Watson−Crick base pair. The structures studied involve the canonical base pair (GC1), rare base-pair tautomers that are formed from GC1 by the antiparallel simultaneous transfer of two protons in hydrogen bonds, and ion-pair structures that are formed by the transfer of a single proton. The geometries of these complexes were optimized by ab initio Hartree−Fock (HF) calculations using the 6-31G* basis set. At the same level, harmonic vibrational frequencies were determined. Nonplanar geometries featuring considerable propeller-twist angles and a pyramidal guanine amino group were found for base pairs involving the guanine anion and 6-hydroxyguanine. The relative stabilities and dissociation energies of the base pairs were determined at the higher MP2/6-31G**//HF/6-31G* level of theory. These methods were also u...

Spontaneous DNA Mutations Induced by Proton Transfer in the Guanine·Cytosine Base Pairs: An Energetic Perspective

The results of an ab initio post Hartree−Fock study of the molecular structures, relative stabilities, and mechanisms of intermolecular proton transfer in isolated, mono- and dihydrated guanine complexes are reported. The geometries of the local minima and transition states were optimized without symmetry restrictions by the gradient procedure at the HF and the MP2 levels of theory and were verified by energy second derivative calculations. The standard 6-31G(d) basis set was used. The single point calculations have been performed at the MP4(SDQ)/6-31G(d)//MP2/6-31G(d) and the MP2/6-311++G(d,p)//MP2/6-31G(d) approximations. All values of total energies have been corrected for zero point energy contributions scaled by a factor of 0.9. The post Hartree−Fock ab initio theory predicts the height of the proton transfer barrier for monohydrated guanine complexes to be approximately two times lower for the tautomeric oxo−hydroxo reactions and approximately three times lower for the reverse hydroxo−oxo reactions ...

Intramolecular Proton Transfer in Mono- and Dihydrated Tautomers of Guanine: An ab Initio Post Hartree−Fock Study

Altogether, 14 amino and imino tautomers of adenine were studied theoretically in the gas phase, in a microhydrated environment (one and two water molecules), and in bulk water environment using the thermodynamic integration method (MD-TI), conductor-like polarizable continuum model (C-PCM, COSMO), and a hybrid model (C-PCM+ one to three explicit water molecules). The structures and relative energies of various tautomers were determined at the RI-MP2 level using the TZVPP basis set. The relative enthalpies at 0 K and relative free energies at 298 K were based on relative energies and zero-point vibration energies, temperature-dependent enthalpy terms, and entropies evaluated at the MP2/6-31G** level. The effect of bulk solvent on the relative stability of adenine tautomers was studied by molecular dynamics free energy calculations using the thermodynamic integration method and self-consistent reaction field. The dipole moment of the canonical form is rather small (2.8 D) but three rare imino tautomers have very large dipole moments (more than 10 D). The canonical form is the global minimum at all theoretical levels in the gas phase, in a microhydrated environment, and in the bulk water. Two unusual rare amino tautomers having hydrogens at N3 and N7, respectively, are less stable in the gas phase by more than 7 kcal/mol and represent the first and the second local minimum. Microhydration, as well as bulk water, stabilizes these unusual tautomers, and the energy gap between them and the canonical form is reduced, but the canonical tautomer remains the global minimum in all three phases. Relative free energies ( T ) 298 K) of these two unusual tautomers in the bulk water evaluated by molecular dynamics free energy calculations are 2.5 and 2.8 kcal/mol, which supports their coexistence in this phase. The C-PCM results agree well with the MD-TI data, and the agreement became close when considering not only the bare tautomers but their complexes with several water molecules representing first solvation shell. Other tautomers are considerably less stable (by 12 -45 kcal/mol), and neither a microhydrated environment nor bulk water can change this unfavorable tautomeric equilibrium. The theoretical data predicting the coexistence of the canonical form and the N3 and the N7 tautomers in bulk water nicely agreed with experimental data obtained from NMR measurements of the adenine tautomers in DMSO (Laxer, A.; Major, D. T.; Gottlieb, H. E.; Fischer, B. J. Org. Chem.2001, 66, 5463.)

Correlated ab Initio Study of Nucleic Acid Bases and Their Tautomers in the Gas Phase, in a Microhydrated Environment, and in Aqueous Solution. Part 3. Adenine

The results of a comprehensive study on the double-proton transfer in Adenine−Thymine (AT) and Guanine−Cytosine (GC) base pairs at room temperature in gas phase and with the inclusion of environmental effects are obtained. The double-proton-transfer process has been investigated in the AT and GC base pairs at the B3LYP/6-31G(d) and MP2/6-31G(d) levels of theory. It has been predicted that the hydrogen-bonded bases possess nonplanar geometries due to sp3 hybridization of nitrogen atoms and because of the soft intermolecular vibrations in the molecular complexes. An analysis of the energetic parameters of the local minima suggests that rare AT base pair conformation is not populated due to the shallowness of this minimum, which completely disappears from the Gibbs free energy surface. The stabilization of canonic or rare forms of the DNA bases by water molecules and metal cations has been predicted by calculating the optimal configuration of charges (using differential product/transition state stabilization...

Double-proton transfer in adenine-thymine and guanine-cytosine base pairs. A post-Hartree-Fock ab initio study.

Both amino-oxo and amino-hydroxy tautomeric forms of 9-methylguanine have been identified in approximately equal abundance in. infrared studies of these molecules isolated in the hydrophobic enviro...

M. Szczesniak

Papers

Infrared spectra of tautomers and rotamers of 9-methylguanine. An experimental and theoretical study