Theoretical Study of the Intramolecular Proton Transfer in the Tautomers of Cytosine Assisted by Water

Ab initio MP2 and DFT studies on the tautomers of cytosine and the related hydrated tautomers have been carried out. The ground‐state structures of four tautomers of cytosine and related transition states were fully optimized. The vibrational frequency analysis was performed on all the optimized structures. Detailed intrinsic reaction coordinate (IRC) calculations were carried out to guarantee the optimized transition‐state structures being connected to the related tautomers. We obtained the relative stability order for the tautomers of cytosine and the related hydrated tautomers. In the isolated and hydrated condition, the bond types of C(2) O(7) and C(4) N(8) greatly affect the stability of the cytosine tautomers. Moreover, we have explored the influence of the water molecules on the intramolecular proton transfer between the keto and enol forms of the cytosine tautomers. The first water molecule obviously decreases the isomerization activation energy for the monohydrated cytosine tautomers. It is shown that the isomerization energy barrier changes only a little when the second and third water molecules are added in the reaction loop. The solvent effects have an obvious influence on the proton‐transfer barrier of the isolated cytosine. However, the solvent effects seem to be insignificant for the isomerization energy barriers of the monohydrated, dihydrated and trihydrated cytosine. The water molecule in these complexes can be looked on as the explicit water. Therefore, the explicit water model may be more credible to explore the intramolecular proton transfer, in comparison with the PCM which is the implicit water model.     

Comprehensive study of the effects of methylation on tautomeric equilibria of nucleic acid bases

Minor tautomers of nucleic acid bases can result by intramolecular proton transfer. These rare tautomers could be stabilized through the addition of methyl groups to DNA bases. A comprehensive theoretical study of tautomers of methylated derivatives of guanine, adenine, cytosine, thymine, and uracil was performed. Molecular geometries of all tautomers were obtained at the density functional theory and MP2 levels with the 6-31G(d,p) basis set, and single-point calculations were performed at the CCSD(T)/6-311G(d,p) level. Tautomers obtained by protonation at the preferred protonation site for methylated isolated bases were compared to their nonmethylated counterparts. The effects of methylation on the relative stabilities of nucleic acid base tautomers are also studied and discussed in this work. The results suggest that some sites on the bases may not be mutagenic and may even stabilize the canonical Watson-Crick form. The results also indicate that a number of methylation sites can stabilize the tautomers, suggesting possible mechanisms for mutagenic changes.     

Solvation free energies of molecules. The most stable anionic tautomers of uracil

Anionic states of nucleic acid bases are suspected to play a role in the radiation damage processes of DNA. Our recent studies suggested that the excess electron attachment to the nucleic acid bases can stabilize some rare tautomers, i.e. imine-enamine tautomers and other tautomers with a proton being transferred from nitrogen sites to carbon sites (with respect to the canonical tautomer). So far, these new anionic tautomers have been characterized by the gas-phase electronic structure calculations and photoelectron spectroscopy experiments. In the current contribution we explore the effect of water solvation on the stability of the new anionic tautomers of uracil. The accurate free energies of solvation are calculated in a two step approach. The major contribution was calculated using the classical free-energy perturbation adiabatic-charging approach, where it is assumed that the solvated molecule has the charge distribution given by the polarizable continuum model. In the second step the free energy of solvation is refined by taking into account the real, average solvent charge distribution. This is done using our accelerated QM/MM simulations, where the QM energy of the solute is calculated in the mean potential averaged over many MD steps. We found that in water solution three of the recently identified anionic tautomers are 6.5-3.6 kcal mol(-1) more stable than the anion of the canonical tautomer.     

The influence of microhydration on the ionization energy thresholds of uracil and thymine

In the present study the ionization energy thresholds (IET's) of uracil and thymine have been calculated (with the B3LYP, PMP2, and P3 levels of theory using the standard 6-31++G(d,p) basis set) with one to three water molecules placed in the first hydration shell. Then (B3LYP) polarizable continuum model (PCM) calculations were performed with one to three waters of the hydration shell included. Calculations show there is a distinct effect of microhydration on uracil and thymine. For uracil, one added water results in a decrease in the IET of about 0.15 eV. The second and third water molecules cause a further decrease by about 0.07 eV each. For thymine, the first water molecule is seen to decrease the IET by about 0.1 eV, while the second and third water molecules cause a further decrease of less than 0.1 eV each. The changes in IET calculated here for thymine with one to three waters of hydration are smaller than the experimental values determined by Kim et al. (Kim, S. K.; Lee, W.; Herschbach, D. R. J. Phys. Chem. 1996, 100, 7933). Preliminary results presented here indicate that the experimental results may involve keto-enol tautomers of thymine. The results of placing the microhydrated structures of uracil and thymine in a PCM cavity was seen to make very little difference in the IET when compared to the IET of ordinary uracil or thymine in a PCM cavity. The implications are that accurate calculations of the IET's of uracil and thymine can be obtained by simply considering long-range solvation effects.     

Solute-solvent interaction in liquids. I. Long-range forces and vibrational solvent shifts

The model of solute— solvent interaction based on dipole-induced-dipole forces (Kirkwood-Bauer-Magat) has been generalized, yielding an expression for the energy as a function of solute position and orientalion within a spherical cavity in a dielectric medium. An analogous relation has been derived for the dispersion energy. Barriers to rotation of the solute molecule and shifts in its vibrational frequency are calculated as functions of cavity radius and eccentricity for the case of dilute solutions of HCl in CCl₄. It is found that the effect of dispersion forces on the vibrational frequency of HCl is two-to-three times more important than the traditional dipole-induced-dipole contribution.     

Tautomerism of pyrimidine bases—uracil,cytosine, isocytosine: Theoretical study with complete optimization of geometry

The semiempirical MINDO /3 method with complete optimization of geometry is employed to calculate the electronic ground-state properties (dipole moments and ionization potentials) and the energies of various tautomeric forms of uracil, uracil monoanion, cytosine, and isocytosine. The results are shown to be consistent with most of the experimental data. Accuracy of various quantum–mechanical methods is discussed. Particular attention is paid to the influence of the geometry optimization on energy differences between various tautomers. Some qualitative conclusions of biological importance are drawn from these calculations.     

Simulations of time-dependent fluorescence in nano-confined solvents

The time-dependent fluorescence of a model diatomic molecule with a charge-transfer electronic transition in confined solvents has been simulated. The effect of confining the solvent is examined by comparing results for solutions contained within hydrophobic spherical cavities of varying size (radii of 10-20 angstroms). In previous work [J. Chem. Phys. 118, 6618 (2002)] it was found that the solute position in the cavity critically affects the absorption and fluorescence spectra and their dependence on cavity size. Here we examine the effect of cavity size on the time-dependent fluorescence, a common experimental probe of solvent dynamics. The present results confirm a prediction that motion of the solute in the cavity after excitation can be important in the time-dependent fluorescence. The effects of solvent density are also considered. The results are discussed in the context of interpreting time-dependent fluorescence measurements of confined solvent systems.     

Influence of excitation and solvation on the shift of tautomeric equilibrium. A quantum-mechanical study

Two quantum-mechanical models are proposed to described a shift of tautomeric equilibrium as a result of electronic excitation and change of environment. According to the first n PD MEP model which is used to estimate the relative solvation effect on the stability of tautomers in an excited state, the calculation of the interaction energy between a solvent (simulated by a set of n point dipoles, n PD) and an excited solute molecule is based on the molecular electrostatic potential (MEP) of the corresponding excited state. In the second n PDQ model, a solvent represented by a set of n point dipoles and quadrupoles (n PDQ) modifies the solute's hamiltonian via an electrostatic interaction contribution. Comparing the results of the calculation for isolated and solvated tautomers, the n PDQ model is used to estimate the influence of electronic excitation on the change of relative stability of tautomers existing in a solution. An application of both models to 2- and 4-oxopyridine predicts a shift of the tautomeric equilibria in their excited states in accordance with experimental evidence.     

Building cavities in a fluid of spherical or rod-like particles: a contribution to the solvation free energy in isotropic and anisotropic polarizable continuum model

A general formalism for the calculation of cavitation energies in the framework of the scaled particle theory has been implemented in the Polarizable Continuum Model (PCM), contributing to the nonelectrostatic part of the molecular free energy in solution. The solute cavity and the solvent molecules are described as hard spherocylinders, whose radius and length are related to the actual molecular shape, while the solvent density is estimated from experimental data, or from the solvent molecular volume, suitably scaled. The present model can describe isotropic solutions of spherical and rod-like molecules in spherical or rod-like solvents, and also anisotropic solutions in which the solvent molecules are oriented in space: in this case, the cavitation energy also depends on the relative orientation of solute and solvent molecules. Test calculations have been performed on simple systems to evaluate the accuracy of the present approach, in comparison with other methods and with the available experimental estimates of the cavitation energy, giving encouraging results.     

Optimum geometries and relative energies for cytosine,thymine, uracil,the imino tautomer of cytosine,the enol tautomer of thymine,and the enol tautomer of uracil by the MINDO/2 SCF MO method

A MINDO /2 SCF MO geometry optimization of cytosine (C), thymine (T), uracil (U), the imino tautomer of cytosine (C*), the enol tautomer of thymine (T*), and the enol tautomer of uracil (U*)was made. The optimized geometries for cytosine, thymine, and uracil agree well with crystallographic data. The optimized geometries for the tautomers show the correct trends in bond lengthening and bond angle except for the C4—O4 length and C4—O4—H angle of T* and U*. The energies of tautomerization were found to be 10.3, ?9.0, and ?14.2 kcal/mol for C?C*, T?T*, and U?U*, respectively, when optimized geometries are used. The overestimation of the C4—O4—H angle is speculated to arise because of an inadequacy in the parametrization of the one-center integrals in MINDO /2.     

Theoretical studies of the tautomeric equilibria for five-member N-heterocycles in the gas phase and in solution

Tautomeric equilibria have been studied for five-member N-heterocycles and their methyl derivatives in the gas phase and in different solvents with dielectric constants of epsilon = 4.7-78.4. The free energy changes differently for tautomers upon solvation as compared to the gas phase, resulting in a shift of the equilibrium constant in solution. Solvents with increasing dielectric constant produce more negative solute-solvent interaction energies and increasing internal energies. The methyl-substituted imidazole and pyrrazole form delicate equilibria between two tautomeric forms. Depending on the solvent, the methyl-substituted triazoles and tetrazole have one or two major tautomers in solution. When estimating the relative solvation free energies by means of an explicit solvent model and using the FEP/MC method, one observes that the preferred tautomers differ in several cases from those predicted by the continuum solvent model. The 1,2-prototropic shift, as an intramolecular tautomerization path, requires about 50 kcal/mol activation energy for imidazole in the gas phase, and this route is also disfavored in a solution. The calculated activation free energy along the intramolecular path is 48-50 kcal/mol in chloroform and water as compared to a literature value of 13.6 kcal/mol for pyrrazole in DMSO. A molecular dynamics computer experiment favors the formation of an imidazole chain in chloroform, making the 1,3-tautomerization feasible along an intermolecular path in nonprotic solvents. In aqueous solution, one strong N-H...Ow hydrogen bond is formed for each species, whereas all other nitrogens in the ring form weaker, N...HwOw type hydrogen bonds. The tetrahydrofuran solvent acts as a hydrogen bond acceptor and forms N-H...Oether bonds. Molecules of the dichloromethane solvent are in favorable dipole-dipole interactions with the solute. The results obtained are useful in the design of N-heterocyclic ligands forming specified hydrogen bonds with protein side chains.     

Hybrid supermolecule-polarizable continuum approach to solvation: Application to the mechanism of the Stevens rearrangement

Semiempirical molecular orbital theory has been used to study the effects of solvation by acetonitrile on the Stevens rearrangement of methylammonium formylmethylide to 2-aminopropanal. Three methods of solvation have been used to investigate both the electrostatic and specific solvent–solute effects of solvation: a supermolecule calculation involving the complete geometry optimization of up to six solvent molecules about the solute, the conductor-like screening model (COSMO) polarizable continuum method which allows for geometry optimization of the solute in a solvent defined by its dielectric constant, and a hybrid method in which up to five solvent molecules are incorporated inside the solute cavity and complete geometry optimization of the complex is carried out within the polarizable continuum. A comparison of the calculated geometries, rearrangement activation energies, and enthalpies of solvation from these approaches is presented, and the explicit versus bulk solvation effects are discussed. The overall effect of all methods for incorporating solvation effects is that the radical pair pathway is perferred over the concerted mechanism. © 1996 by John Wiley & Sons, Inc.     

Enthalpies of solvation of alkylated uracils in water,nonaqueous and mixed solvents

The enthalpies of solution of uracil and its alkylated derivatives in water, methanol, N,N-dimethylformamide (DMF) and water+DMF mixtures were measured at 25°C. The enthalpies of solvation were determined. The enthalpies of cavity formation, corresponding to the enthalpies of solvent-solvent interactions were calculated and the enthalpies of solute-solvent interactions were obtained. The presence of the alkyl groups was found to have different effects on the enthalpy of interaction depending on the position and size of the substitution. The effect of alkylation at the nonpolar side of the uracil ring was found to arise mostly from the enhancement of the van der Waals interactions. The alkyl substitutions at the polar side resulted also in the removal of the solvent molecules interacting specifically with the polar groups of uracil. The enthalpy of those specific interactions was determined and found to be stronger in methanol and DMF than in water. Enthalpies of solvation in the binary water+DMF solvent were found to depend in a nonlinear way on the solvent composition. The nonlinearities in the water-rich region were found to arise from the decay of the hydrophobic hydration of the solutes with the increasing DMF content. The substitution of two methyl groups caused the uracil molecule to bahave as a predominantly hydrophobic solute. The nonlinearities in the DMF-rich region were found only for those solutes which can form hydrogen bonds with DMF.     

Tautomerism of oxopyridines and oxopyrimidines: Theoretical study with complete optimization of geometry

The semiempirical MINDO /3 method is employed to calculate the energies of various tautomers of model tautomeric compounds— 2-oxo- and 4-oxopyridines and pyrimidines. The results are compared with experimental data in the gas phase, where the solute–solvent interactions not included in theoretical calculations are absent. Although the relative energies obtained by the MINDO /3 method appear to be superior to other semiempirical and ab initio calculations, the accuracy of the method was determined to be as low as 3–4 kcal/mol. It indicates that it is exceedingly difficult to account theoretically for intrinsic stabilities of the tautomers. The importance of various factors influencing calculated free-energy differences is discussed. Particular attention is paid to the problem of geometry optimization.     

How to model solvent effects on molecular properties using quantum chemistry? Insights from polarizable discrete or continuum solvation models

We present a comparative study of solvent effects on the 15N NMR shielding constants and the lowest electronic excitation energy (n --> pi*) in the three diazines (pyrazine, pyrimidine, and pyridazine) in aqueous solution. This solvent is modeled using either a polarizable continuum model (PCM) or a discrete polarizable model (DPM). We analyze the results obtained with the two models in terms of differences/similarities in the reaction field produced at the solute. The PCM reaction field is found to be quite sensitive to the dimension of the cavity and so are the molecular properties. However, constructing the cavity so that the DPM and PCM reaction fields become similar in magnitude leads to quite similar results for the studied molecular properties modeling the solvent using either the PCM or the DPM. Compared to experimental data, the most accurate predicted results are obtained by describing the closest water molecules at the same level of sophistication as that of the solute, whereas the bulk solvent may be described using either PCM or MM. Finally, a comparison with geometry-optimized clusters seems to show that it is important to check potential deficiencies in the force field in order for this to treat hydrogen bonding in a consistent manner.     

分子动力学模拟纳米尺寸限制体系下氩溶液中I2的振动能量弛豫

利用平衡态分子动力学方法(EMD)模拟了纳米尺寸限制球壳内I2在Ar溶液中的振动能量转移. 计算并讨论了I2振动能量弛豫时间T1随球壳半径、溶剂密度的变化规律. 通过分子间相互作用分析, 在原子、分子水平上, 揭示了随着球壳半径的减小, T1呈逐渐增大趋势的原因. 结果表明, 球壳的几何限制效应和表面作用对受限溶液密度分布的影响较大, 从而导致溶质振动弛豫的显著变化. 此外, 非限制体系模拟显示, 非平衡态分子动力学(NEMD)方法可以得到与平衡态分子动力学方法较一致的振动能量弛豫时间T1.     

Transient cavities and the excess chemical potentials of hard-spheroid solutes in dipolar hard-sphere solvents

Monte Carlo computer simulations are used to study transient cavities and the solvation of hard-spheroid solutes in dipolar hard-sphere solvents. The probability distribution of spheroidal cavities in the solvent is shown to be well described by a Gaussian function, and the variations of fit parameters with cavity elongation and solvent properties are analyzed. The excess chemical potentials of hard-spheroid solutes with aspect ratios x in the range of 15< or =x< or =5, and with volumes between 1 and 20 times that of a solvent molecule, are presented. It is shown that for a given molecular volume and solvent dipole moment (or temperature) a spherical solute has the lowest excess chemical potential and hence the highest solubility, while a prolate solute with aspect ratio x should be more soluble than an oblate solute with aspect ratio 1x. For a given solute molecule, the excess chemical potential increases with increasing temperature; this same trend can be observed in hydrophobic solvation. A scaled-particle theory based on the solvent equation of state and a fitted solute-solvent interfacial tension shows excellent agreement with the simulation results over the whole range of solute elongations and volumes considered. An information-theoretic model based on the solvent density and radial distribution function is less successful, being accurate only for small solute volumes and low solvent densities.     

Excited states dipole moments and polarizabilities of uracil and cytosine 5-halo derivatives

Dipole moments and polarizabilities of different excited states of uracil and cytosine 5-halo derivatives have been calculated using solvent shift methods and CNDO/S calculations. The results are discussed in relation to different solute–solvent interactions and the nature of the electronic transition.     

Thin‐Film Properties of DNA and RNA Bases: A Combined Experimental and Theoretical Study

The structures of the DNA and RNA bases cytosine, uracil, and thymine in thin films with a nominal film thickness of about 20 nm are studied by using X‐ray photoemission spectroscopy (XPS) and Fourier‐transform infrared spectroscopy. The molecules are evaporated in situ from powder on a gold foil. The experimental results indicate that cytosine is composed of two energetically close tautomeric forms, whereas uracil and thymine exist in only one tautomeric form. Additionally, quantum chemical calculations are performed to complement the experimental results. The relative energies of the tautomeric forms of cytosine, uracil, and thymine are calculated using Hartree–Fock (HF), density functional theory (DFT), and post‐HF methods. Furthermore, the assignment of the XPS spectra is supported by using simple model considerations employing Koopmans ionization energies and Mulliken net atomic charges.     

Interaction with glycine increases stability of a mutagenic tautomer of uracil. A density functional theory study

The most stable structures for the gas-phase complexes of minor tautomers of uracil (U) with glycine (G) were characterized at the density functional B3LYP/6-31++G level of theory. These are cyclic structures stabilized by two hydrogen bonds. The relative stability of isolated tautomers of uracil was rationalized by using thermodynamic and structural arguments. The stabilization energies for complexes between the tautomers of U and G result from interplay between the stabilizing two-body interaction energies and destabilizing one-body terms. The latter are related to the energies of (i) tautomerization of the unperturbed moieties and (ii) distortions of the resulting rare tautomers in the complex. The two-body term describes the interaction energy between distorted tautomers. The two-body interaction energy term correlates with perturbations of length of the proton-donor bonds as well as with deprotonation enthalpies and proton affinities of the appropriate monomer sites. It was demonstrated that the relative instability of rare tautomers of uracil is diminished due to their interactions with glycine. In particular, the instability of the third most stable tautomer (U(III)) is decreased from 11.9 kcal/mol for non-interacting uracil to 6.7 kcal/mol for uracil in a complex with the zwitterionic tautomer of glycine. A decrease of instability by 5.2 kcal/mol could result in an increase of concentration of U(III) by almost 5 orders of magnitude. This is the tautomer with proton donor and acceptor sites matching guanine rather than adenine. Moreover, kinetic characteristics obtained for the glycine-assisted conversion of the most stable tautomer of uracil (U(I)) to U(III) indicate that the U(I)<-->U(III) thermodynamic equilibrium could be easily attained at room temperature. The resulting concentration of this tautomer falls in a mutationally significant range.