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

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 rninimum. 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-Tl 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. Client. 2001, 66, 5463.).