Binding of cationic and neutral phenanthridine intercalators to a DNA oligomer is controlled by dispersion energy: quantum chemical calculations and molecular mechanics simulations.

Correlated ab initio as well as semiempirical quantum chemical calculations and molecular dynamics simulations were used to study the intercalation of cationic ethidium, cationic 5-ethyl-6-phenylphenanthridinium and uncharged 3,8-diamino-6-phenylphenanthridine to DNA. The stabilization energy of the cationic intercalators is considerably larger than that of the uncharged one. The dominant energy contribution with all intercalators is represented by dispersion energy. In the case of the cationic intercalators, the electrostatic and charge-transfer terms are also important. The DeltaG of ethidium intercalation to DNA was estimated at -4.5 kcal mol(-1) and this value agrees well with the experimental result. Of six contributions to the final free energy, the interaction energy value is crucial. The intercalation process is governed by the non-covalent stacking (including charge-transfer) interaction while the hydrogen bonding between the ethidium amino groups and the DNA backbone is less important. This is confirmed by the evaluation of the interaction energy as well as by the calculation of the free energy change. The intercalation affects the macroscopic properties of DNA in terms of its flexibility. This explains the easier entry of another intercalator molecule in the vicinity of an existing intercalation site.

Mutagenic properties of 5-halogenuracils: correlated quantum chemical ab initio study.

The relative stability of all possible 5-bromouracil tautomers was studied theoretically in a gas phase, in a microhydrated environment (with one water molecule), and in bulk water. Tautomer structures were determined by gradient optimization at the correlated ab initio quantum chemical level with an extended basis set of atomic orbitals. The role of water was examined by using a self-consistent reaction field method. The relative stabilization and free energies in the gas phase, the microhydrated environment, and the bulk water clearly support the preference of the canonical keto form of 5-bromouracil in all mentioned environments. An increased abundance of enol tautomers when passing from uracil to 5-bromouracil is not supported by our calculations. Thus, the tautomeric model of the mutagenic activity of 5-bromouracil proposed previously [Hu et al. Biochemistry (2004) 43, 6361] can be refuted. The validity of other mutagenic models was also discussed, and finally a new mechanism for explaining the mutagenic activity of halogenuracils based on their different behaviors in triplet excited states was suggested.

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.

Correlated ab initio study of nucleic acid bases and their tautomers in the gas phase, in a microhydrated environment and in aqueous solution. guanine: surprising stabilization of rare tautomers in aqueous solution.

Altogether eight keto and enol tautomers of guanine were studied theoretically in the gas phase, in a microhydrated environment (1 and 2 water molecules) and in bulk water. The structures of isolated, as well as mono- and dihydrated tautomers were determined by means of the RI-MP2 method using the extended TZVPP (5s3p2d1f/3s2p1d) basis set. The relative energies of isolated tautomers included the correction to higher correlation energy terms evaluated at the CCSD(T)/aug-cc-pVDZ level. The relative enthalpies at 0 K and relative free energies at 298 K were based on the above-mentioned relative energies and zero-point vibration energies, temperature-dependent enthalpy terms and entropies evaluated at the MP2/6-31G level. The keto form having hydrogen atom at N7 is the global minimum while the canonical form having hydrogen atom at N9 represents the first local minimum at all theoretical levels in vacuo and in the presence of 1 and 2 water molecules. All three unusual rare tautomers having hydrogens at N3 and N7, at N3 and N9, and also at N9 and N7 are systematically considerably less stable and can be hardly detected in the gas phase. The theoretical predictions fully agree with existing theoretical as well as experimental results. The effect of bulk solvent on the relative stability of guanine tautomers was studied by self-consistent reaction field and molecular dynamics free energy calculations using the thermodynamic integration method. Bulk solvent, surprisingly, strongly favored these three rare tautomers over all remaining low-energy tautomers and probably only these forms can exist in water phase. The global minimum (tautomer with hydrogens at N3 and N7) is by 13 kcal/mol more stable than the canonical form (3rd local minimum). Addition of one or two water molecules does not change the relative stability order of isolated guanine tautomers but the respective trend clearly supports the surprising stabilization of three rare forms.