Filip Ryjáček

Correlated ab initio study of nucleic acid bases and their tautomers in the gas phase, in a microhydrated environment and in aqueous solution. Part 4. Uracil and thymine.

Altogether 13 keto and enol tautomers of uracil and 13 keto and enol tautomers of thymine were studied theoretically in the gas phase, in a microhydrated environment (1 and 2 water molecules) and in a water environment. Bulk water was described using the thermodynamic integration method, Conductor-like polarizable continuum model (C-PCM, COSMO) and hybrid model (C-PCM + 1-2 explicit water molecules). The structures of various tautomers were determined at the RI-MP2 level using the TZVPP basis set while relative energies were determined at the CCSD(T) level. The relative free energies at 298 K were based on the relative energies mentioned above and zero-point vibration energies, and temperature dependent enthalpy terms and entropies evaluated at the MP2/6-31G** level. The effect of bulk solvent on the relative stability of uracil and thymine tautomers was studied using molecular dynamics free energy calculations by means of the thermodynamic integration method and self-consistent reaction field. Despite the completely different nature of these methods they provide comparable solvation free energies. Besides theoretical investigation, experimental detection of uracil and thymine tautomers was performed by means of steady-state fluorescence. We conclude that it is impossible to utilize the method used by Suwaiyan and Morsy (M. A. Morsy, A. M. Al-Somali and A. Suwaiyan, J. Phys. Chem. B, 1999, 103(50), 11205) for tautomer detection, even if a very sensitive fluorimeter is used. Theoretical relative energies and free energies for isolated uracil and thymine tautomers support the existence of the canonical form only. The microhydrated environment and bulk solvent stabilize enol forms more than the canonical keto one, but gas phase destabilization of these enol forms is too high. Population of rare enol forms of uracil and thymine in bulk water will thus be very low and canonical structure will also be dominant in this phase.

Already two water molecules change planar H-bonded structures of the adenine···thymine base pair to the stacked ones: a molecular dynamics simulations study

The dynamical structure of the adenine···thymine nucleic acid base pair exposed to a small number of water molecules (from 1 to 216) was determined using molecular dynamics simulations with Cornell et al. force field (W. D. Cornell, P. Cieplak, C. I. Bayly, I. R.Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. E. Caldwell and P. Kollman, J. Am. Chem. Soc., 1995, 117, 5179). The gradual increase of hydration number results in a transition from planar base pair structures to nonplanar ones, and already for two water molecules the population of stacked structures is higher than that of planar structures.

New Parameterization of the Cornell et al. Empirical Force Field Covering Amino Group Nonplanarity in Nucleic Acid Bases

The Cornell et al. empirical potential (Cornell et al., J Am Chem Soc 1995, 117, 5197) was modified by the introduction of nonplanarity of the amino group in guanine, adenine, and cytosine. Reparameterization was performed for 12 bond parameters of the amino group (three valence angles (C–N–H1, C–N–H2, and H1–N–H2) and the improper dihedral angle at nitrogen, four dihedral angles (X–C–N–H1, Y–C–N–H2, X–X–C–N, Y–Y–C–N), three valence angles (X–C–N, Y–C–N, X–C–Y), and the improper dihedral angle at the adjacent carbon), and was based on correlated ab initio potential energy surfaces. Calculations were performed using the resolution of identity MP2 (RIMP2) method with SVP (3s2p1d/2s1p), TZVP (5s3p1d/3s1p), TZVPP (5s3p2d1f/3s2p1d), and augTZVPP (6s4p3d2f/4s3p2d) basis sets. Results obtained on the latter two levels are practically identical with the literature reference data [MP2/6‐311++G(2df,p)] and the RIMP2/augTZVPP data can be considered a new reference set. The potential energy surface used for reparameterization was evaluated at the RIMP2/SVP level because respective geometry as well as energy data were close to the reference ones, and the computational time was very favorable. The modified potential was tested for 19 H‐bonded and eight stacked nucleic acid base pairs. Interaction energies as well as geometries were described by the modified potential considerably better than by the original one and significant improvement resulted in the description of the nonplanar H‐bonded and stacked complexes.

Adenine⋯2,4-difluorotoluene (modified base) pair: potential and free-energy surfaces: Non-empirical and empirical potential studies

Abstract Ab initio calculations are described for bonded and stacked structures of adenine⋯2,4-difluorotoluene. Stabilization energies are determined with inclusion of correlation energy at the MP2/6-31G ∗ (0.25) level. Stacked structures of the pair are more stable than planar ones. The nucleic acid force field of Cornell et al. reproduces ab initio stabilization energies of planar and stacked structures well. The population of various structures of the pair, which is proportional to Δ G of base pair formation, was determined by long runs of molecular dynamics with the force field of Cornell et al. Potential- and free-energy surfaces are similar and, among 11 of the most populated dimer structures, there is no planar H-bonded structure.