A theoretical study of hydration of 4-thiouracil in the electronic singlet excited state

Abstract

A comprehensive theoretical investigation was performed to study the interaction of water molecules with 4-thiouracil (4TU) in the ground and electronic lowest singlet nπ* excited state. The studied system included the isolated 4TU and the hydrated complexes of 4TU with one, two and three water molecules. The interacting water molecules were placed in between different hydrogen bond donating and accepting sites of 4TU. The ground state geometries were optimized at the HF level using the 6-311++G(d,p) basis set. The electronic excited state geometries of 4TU and different hydrated complexes were optimized at the CI-singles (CIS) level using the 6-311++G(d,p) basis set. The harmonic vibrational frequency calculations were performed to ascertained stationary points at the respective potential energy surfaces; all geometries were found minima. The lowest singlet nπ* transition of 4TU was assigned to the excitation of the lone-pair electron of the thiocarbonyl group to π*-antibonding orbitals of the molecule. It was found that the nπ* state provides a repulsive potential for water binding in the excited state. Therefore, the structures of the hydrated complexes, where water molecule was bonded at the thiocarbonyl group, were remarkably modified in the electronic singlet nπ* excited state as compared to the corresponding structure in the ground state. Further, in going from the ground state to the excited state significant changes in the features of molecular electrostatic potentials are also revealed.

Introduction

The molecular structure of DNA consists of left-handed helical stacked complementary pair of nitrogenous bases (adenine, guanine, thymine and cytosine) supported by a sugar molecule and the phosphate backbone. In RNA, thymine is replaced by the uracil. It is generally believed that any structural modification of bases may lead to mutation. The thio analogs of nucleic acid bases have remarkably different biological and pharmacological activities from the parent compounds [1], [2], [3], [4], [5]. For example, the 6-thioguanine is suggested to block the formation of G-tetrads in the guanine rich oligodeoxyribonucleotides [6]. The 4-thiothymidine is responsible for the double helical structure in the form of the reversed Hoogsteen base pair [7]. Several thiobases have varieties of therapeutic activities. For example, thiouracils have been suggested as anticancer and antithyroid drugs [2]. The thio analogs of dUMP are known as good substrates of thymidilate synthase [8]. It is well know that the sulfur is a weaker hydrogen bond acceptor that the oxygen atom. Therefore, hydrations of thiocarbonyl containing species are destabilized as compared to the corresponding carbonyl containing species [9]. The photophysical properties are also significantly modified with the sulfur substitution. The thiocarbonyl compounds have lower electronic excitation energies than the corresponding carbonyl compounds [10].

Different theoretical and experimental investigations were performed to determine the structural and tautomeric properties of thio analogs of uracil [1], [7], [11], [12], [13], [14]. Nowak et al. [1] have provided a comprehensive analysis of different theoretical and experimental investigations on thiouracils in a recent review article. All theoretical calculations on different thiouracil have predicted the existence of only ketothione (dithione in 2,4-dithiouracil) tautomer in the gas phase and in water solution. The thio derivatives of uracil in the crystalline form and in low temperature inert matrixes are also found to exist in the ketothione tautomeric form [7], [15], [16], [17]. Results from different theoretical and experimental studies on 4TU show the existence of only ketothione tautomer in the gas phase and in water solution [1], [2], [7], [11], [13], [18], [19], [20]. However, the indication of the existence of minor tautomeric form in the ethanol solution is also revealed [18]. Recently, we have performed a multiconfigurational self-consistent field (MCSCF) study including the dynamic electron correlation effect based on the second-order multiconfigurational quasi-degenerate perturbation (MCQDPT2) theory on the excited state properties of 4TU in the gas phase [21]. Based on the MCSCF study, a significant charge transfer from the sulfur atom to the ring heavy atoms of 4TU was revealed in the vertical singlet and triplet nπ* excited state. An extensive experimental absorption, circular dichroism (CD) and magnetic circular dichroism (MCD) investigations on different thiouracil and substituted analogs were performed by Igarashi-Yamamoto et al. [20] in the water and acetonitrile solutions. The experimental transitions of 2-thiouracil and 2,4-dithiouracil were explained in terms of the thione–thiol tautomeric form, however, the 4TU was found to exist only in the ketothione tautomeric form. Recently, we have performed a very extensive theoretical calculation on different thiouracils and their methyl derivatives including different tautomers and ionic forms in the gas phase and in water and acetonitrile solutions at the time-dependent density functional theory (TDDFT) level to compute electronic singlet and triplet transition energies and also to resolve the existing controversies on the thione–thiol tautomerism of thiouracils in different environments [22]. We have shown that thiouracils would exist mainly in the ketothione tautomeric form in the gas phase and in solutions and the consideration of thiol tautomeric form is not needed to explain the experimental transition energies. Further, the spectral features of 2,4-dithiouracil were found to be complex and the existence of anionic form of the molecule was also suggested in the water and acetonitrile solutions.

Water is ubiquitous and plays an important role in the structures and functions of biomolecular systems. Water bridges can govern the proton transfer reactions between acid and base sites lying far away from each other in biological systems [23], [24]. The hydrated complexes are found to undergo profound structural modifications under electronic excitations, especially in the electronic nπ* excited state. It has been shown experimentally that adenine–water hydrogen bond is dissociated in the nπ* excited state [25], [26]. We have shown theoretically that the hydration structure of cytosine is significantly modified in the nπ* excited state [27], [28]. Further, a significant role of the nπ* state has also been suggested in the ultrafast nonradiative deactivation of nucleic acid bases [29]. The lowest singlet electronic excited state of thiouracils is of the nπ* type [20], [21], [22].

In the present work, we have performed a comprehensive theoretical calculation on the hydration of 4TU in the lowest singlet nπ* excited state through the excited state geometry optimizations. The studied systems included hydrated complexes with one, two and three water molecules in the first solvation shell of 4TU. The nature of molecular electrostatic potentials in the ground and vertical and relaxed singlet nπ* excited states was also investigated.