No abstract

To provide an in-depth insight into the molecular basis of spontaneous tautomerism in DNA and RNA base pairs, a hybrid Monte Carlo (MC)-quantum chemical (QC) methodology is implemented to map two-dimensional potential energy surfaces along the reaction coordinates of solvent-assisted proton transfer processes in guanosine and its analog acyclovir in aqueous solution. The solvent effects were simulated by explicit inclusion of water molecules that model the relevant part of the first hydration shell around the solute. The position of these water molecules was estimated by carrying out a classical Metropolis Monte Carlo simulation of dilute water solutions of the guanosine (Gs) and acyclovir (ACV) and subsequently analyzing solute-solvent intermolecular interactions in the statistically-independent MC-generated configurations. The solvent-assisted proton transfer processes were further investigated using two different ab initio MP2 quantum chemical approaches. In the first one, potential energy surfaces of the 'bare' finite solute-solvent clusters containing Gs/ACV and four water molecules (MP2/6-31+G(d,p) level) were explored, while within the second approach, these clusters were embedded in 'bulk' solvent treated as polarizable continuum (C-PCM/MP2/6-31+G(d,p) level of theory). It was found that in the gas phase and in water solution, the most stable tautomer for guanosine and acyclovir is the 1H-2-amino-6-oxo form followed by the 2-amino-6-(sZ)-hydroxy form. The energy barriers of the water-assisted proton transfer reaction in guanosine and in acyclovir are found to be very similar - 11.74 kcal mol for guanosine and 11.16 kcal mol for acyclovir, and the respective rate constants (k = 1.5 × 10 s, guanosine and k = 4.09 × 10 s, acyclovir), are sufficiently large to generate the 2-amino-6-(sZ)-hydroxy tautomer. The analysis of the reaction profiles in both compounds shows that the proton transfer processes occur through the asynchronous concerted mechanism.

Altogether six tautomers of cytosine and three tautomers of cytidine and deoxycytidine are studied theoretically in the gas phase and in a microhydrated environment. Their structures are optimized at MP2/6-31 + G(d,p) level. The relative energies of the isolated and the hydrated tautomers included the correction to higher correlation energy terms evaluated at the SCS-MP2, MP4, and CCSD(T) levels. The free energies at 298 K and higher temperatures are based on the above-mentioned relative energies and temperature-dependent enthalpy terms and entropies evaluated at the MP2/6-31 + G(d,p) level. Theoretical predictions for the coexistence of five species for cytosine in the gas phase (canonical, trans-and cis-enol-amino, transand cis-imino-oxo forms) fully agree with recent experimental results. Five-hydrated cytosine tautomeric forms of are investigated at CPCM/SCS-MP2/6-31 + G(d,p) level to evaluate the interconversion barriers between them and to explain the coexistence, experimentally proven, of two amino-oxo and one imino-oxo tautomers of cytosine in aqueous solution. The presence of coordinated water molecules acting as a catalyst make the tautomerization processes quite easier. It appeared clear from the obtained data that the influence of the hydrogen-bonded water molecules as well as the introduction of solvent effects in reducing the height of the tautomerization barriers for these five-hydrated systems is quite substantial. Similar results are obtained for the tri-hydrated cytidine and the 2-deoxycytidine tautomeric forms. In aqueous solution of cytidine, syn-and syn-clinal-conformers оf the amino-oxo tautomer should coexist with small amounts of syn-and syn-clinal conformers оf iminooxo tautomer. For 2-deoxycytidine an equilibrium has been found to exist between the syn-and anti-conformers of the amino-oxo and the imino-oxo tautomers. The water-assisted proton transfer reactions released through asynchronous concerted mechanism and the conformation of the sugar ring in nucleosides does not change during the tautomerization.