On the unusual stability of valence anions of thymine based on very rare tautomers: A computational study

We characterized anionic states of thymine using various electronic structure methods, with the most accurate results obtained at the CCSD(T)/aug-cc-pVDZ level of theory followed by extrapolations to complete basis set limits. We found that the most stable anion in the gas phase is related to an imino-oxo tautomer, in which the N1H proton is transferred to the C5 atom. This valence anion, aT(c5)(nl), is characterized by an electron vertical detachment energy (VDE) of 1251 meV and it is adiabatically stable with respect to the canonical neutral nT(can) by 2.4 kcal/mol. It is also more stable than the dipole-bound (aT(dbs)(can)), and valence anion aT(val)(can) of the canonical tautomer. The VDE values for aT(dbs)(can)and T(val)(can) are 55 and 457 meV, respectively. Another, anionic, low-lying imino-oxo tautomer with a VDE of 2458 meV has a proton transferred from N3H to C5 aT(c5)(n3). It is less stable than aT(val)(can) by 3.3 kcal/mol. The mechanism of formation of anionic tautomers with the carbons C5 or C6 protonated may involve intermolecular proton transfer or dissociative electron attachment to the canonical neutral tautomer followed by a barrier-free attachment of a hydrogen atom to C5. The six-member ring structure of the anionic tautomers with carbon atoms protonated is unstable upon an excess electron detachment. Within the PCM hydration model, the low-lying valence anions become adiabatically bound with respect to the canonical neutral; becomes the most stable, being followed by aT(c5)(nl), aT(c5)(n3), aT(can), and aT(c5)(nl).     

Valence and dipole-bound anions of the most stable tautomers of guanine

Anionic states of guanine, which is the only nucleic acid base of which the anions have not yet been studied in either photoelectron spectroscopic (PES) or Rydberg electron transfer (RET) experiments, have been characterized for the four most stable tautomers of neutral guanine using a broad spectrum of electronic structure methods from the density functional theory, with the B3LYP exchange-correlation functional, to the coupled-cluster method, with single, double, and perturbative triple excitations. Both valence and dipole-bound anionic states were addressed. We identified some of the difficulties facing future PES or RET experiments on the anion of guanine. Even if guanine is successfully transferred to the gas phase without thermal decomposition, it is critical to have the canonical amino-oxo (G) and both amino-hydroxy (GH and GHN7H) tautomers in the beam, not only the most stable, a noncanonical, amino-oxo tautomer (GN7H), as the latter does not support an adiabatically bound anionic state. We also suggested a scheme for enrichment of gas-phase guanine with the canonical tautomer, which is not the most stable in the gas phase, but which is of main interest due to its biological relevance. The tautomers G, GN7H, and GHN7H support vertically bound valence anionic states with the CCSD(T) value of vertical detachment energy of +0.58, +0.21, and +0.39 eV, respectively. These anionic states are, however, adiabatically unbound and thus metastable. The vertical electronic stability of these valence anionic states is accompanied by serious "buckling" of the molecular skeleton. The G and GHN7H tautomers support dipole-bound states with the CCSD(T) values of adiabatic electron affinity of 65 and 36 meV, respectively. A contribution from higher-than-second-order correlation terms represents, respectively, 48 and 68% of the total vertical electron detachment energy determined at the CCSD(T) level.     

Photoelectron spectrum of valence anions of uracil and first-principles calculations of excess electron binding energies

The photoelectron spectrum (PES) of the uracil anion is reported and discussed from the perspective of quantum chemical calculations of the vertical detachment energies (VDEs) of the anions of various tautomers of uracil. The PES peak maximum is found at an electron binding energy of 2.4 eV, and the width of the main feature suggests that the parent anions are in a valence rather than a dipole-bound state. The canonical tautomer as well as four tautomers that result from proton transfer from an NH group to a C atom were investigated computationally. At the Hartree-Fock and second-order Moller-Plesset perturbation theory levels, the adiabatic electron affinity (AEA) and the VDE have been converged to the limit of a complete basis set to within +/-1 meV. Post-MP2 electron-correlation effects have been determined at the coupled-cluster level of theory including single, double, and noniterative triple excitations. The quantum chemical calculations suggest that the most stable valence anion of uracil is the anion of a tautomer that results from a proton transfer from N1H to C5. It is characterized by an AEA of 135 meV and a VDE of 1.38 eV. The peak maximum is as much as 1 eV larger, however, and the photoelectron intensity is only very weak at 1.38 eV. The PES does not lend support either to the valence anion of the canonical tautomer, which is the second most stable anion, and whose VDE is computed at about 0.60 eV. Agreement between the peak maximum and the computed VDE is only found for the third most stable tautomer, which shows an AEA of approximately -0.1 eV and a VDE of 2.58 eV. This tautomer results from a proton transfer from N3H to C5. The results illustrate that the characteristics of biomolecular anions are highly dependent on their tautomeric form. If indeed the third most stable anion is observed in the experiment, then it remains an open question why and how this species is formed under the given conditions.     

Barrier-free proton transfer in the valence anion of 2'-deoxyadenosine-5'-monophosphate. II. A computational study

The propensity of four representative conformations of 2(')-deoxyadenosine-5(')-monophosphate (5(')-dAMPH) to bind an excess electron has been studied at the B3LYP6-31++G(d,p) level. While isolated canonical adenine does not support stable valence anions in the gas phase, all considered neutral conformations of 5(')-dAMPH form adiabatically stable anions. The type of an anionic 5(')-dAMPH state, i.e., the valence, dipole bound, or mixed (valence/dipole bound), depends on the internal hydrogen bond(s) pattern exhibited by a particular tautomer. The most stable anion results from an electron attachment to the neutral syn-south conformer. The formation of this anion is associated with a barrier-free proton transfer triggered by electron attachment and the internal rotation around the C4(')-C5(') bond. The adiabatic electron affinity of the a_south-syn anion is 1.19 eV, while its vertical detachment energy is 1.89 eV. Our results are compared with the photoelectron spectrum (PES) of 5(')-dAMPH(-) measured recently by Stokes et al., [J. Chem. Phys. 128, 044314 (2008)]. The computational VDE obtained for the most stable anionic structure matches well with the experimental electron binding energy region of maximum intensity. A further understanding of DNA damage might require experimental and computational studies on the systems in which purine nucleotides are engaged in hydrogen bonding.     

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.     

Coupled-cluster and explicitly correlated perturbation-theory calculations of the uracil anion

A valence-type anion of the canonical tautomer of uracil has been characterized using explicitly correlated second-order Moller-Plesset perturbation theory (RI-MP2-R12) in conjunction with conventional coupled-cluster theory with single, double, and perturbative triple excitations. At this level of electron-correlation treatment and after inclusion of a zero-point vibrational energy correction, determined in the harmonic approximation at the RI-MP2 level of theory, the valence anion is adiabatically stable with respect to the neutral molecule by 40 meV. The anion is characterized by a vertical detachment energy of 0.60 eV. To obtain accurate estimates of the vertical and adiabatic electron binding energies, a scheme was applied in which electronic energy contributions from various levels of theory were added, each of them extrapolated to the corresponding basis-set limit. The MP2 basis-set limits were also evaluated using an explicitly correlated approach, and the results of these calculations are in agreement with the extrapolated values. A remarkable feature of the valence anionic state is that the adiabatic electron binding energy is positive but smaller than the adiabatic electron binding energy of the dipole-bound state.     

Negatively charged xanthine. I. Anions formed by canonical isomers

The possibility of an excess electron binding to canonical isomers of xanthine in the gas phase was studied at the coupled-cluster level with single and double excitations using the 6-31++G** basis sets supplemented with the 4(sp)3d set of diffuse functions. It was found that xanthine should exist in the gas phase as one canonical tautomer while all the other tautomers are not likely to be detected experimentally because of their significant thermodynamic instability. On the other hand, all canonical tautomers (except one) were found to be capable of forming electronically stable anionic states of dipole-bound nature. However, the only thermodynamically stable anion (with vertical electron binding energy estimated to be 0.041 eV) based on xanthine tautomers is the one supported by the most stable neutral species.     

Photoelectron spectroscopy of adiabatically bound valence anions of rare tautomers of the nucleic acid bases

Anionic states of nucleic acid bases (NABs) are involved in DNA damage by low-energy electrons and in charge transfer through DNA. Previous gas phase studies of free, unsolvated NAB parent anions probed mostly dipole-bound states, which are not present in condensed phase environments. Recently, we demonstrated that very rare tautomers of uracil (U), cytosine (C), adenine (A), and guanine (G), which are obtained from canonical tautomers through N-to-C proton transfers, support valence anionic states. Here we report the photoelectron spectrum of the final member of the NABs series: the valence state of the thymine (T) anion. Additionally, we summarized the work of all five NABs. All of the newfound anionic tautomers of the NABs may be formed via dissociative electron attachment followed by hydrogen atom reattachment to a carbon atom. Furthermore, these unusual tautomers may affect the structure and properties of DNA and RNA exposed to low-energy electrons. The new valence states observed here, unlike dipole bound states, could exist in condensed phases and may be relevant to radiobiological damage.     

Gas-phase thermochemical properties of pyrimidine nucleobases

The gas-phase acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine have been examined using both theoretical (B3LYP/6-31+G*) and experimental (bracketing, Cooks kinetic) methods. This paper represents a comprehensive examination of multiple acidic sites of thymine and cytosine and of the acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine. Thymine exists as the most stable "canonical" tautomer in the gas phase, with a DeltaH(acid) of 335 +/- 4 kcal mol(-1) (DeltaG(acid) = 328 +/- 4 kcal mol(-1)) for the more acidic N1-H. The acidity of the less acidic N3-H site has not, heretofore, been measured; we bracket a DeltaH(acid) value of 346 +/- 3 kcal mol(-1) (DeltaG(acid) = 339 +/- 3 kcal mol(-1)). The proton affinity (PA = DeltaH) of thymine is measured to be 211 +/- 3 kcal mol(-1) (GB = DeltaG = 203 +/- 3 kcal mol(-1)). Cytosine is known to have several stable tautomers in the gas phase in contrast to in solution, where the canonical tautomer predominates. Using bracketing methods in an FTMS, we measure a DeltaH(acid) for the more acidic site of 342 +/- 3 kcal mol(-1) (DeltaG(acid) = 335 +/- 3 kcal mol(-1)). The DeltaH(acid) of the less acidic site, previously unknown, is 352 +/- 4 kcal mol(-1) (345 +/- 4 kcal mol(-1)). The proton affinity is 228 +/- 3 kcal mol(-1) (GB = 220 +/- 3 kcal mol(-1)). Comparison of these values to calculations indicates that we most likely have a mixture of the canonical tautomer and two enol tautomers and possibly an imine tautomer under our conditions in the gas phase. We also measure the acidity and proton affinity of cytosine using the extended Cooks kinetic method. We form the proton-bound dimers via electrospray of an aqueous solution, which favors cytosine in the canonical form. The acidity of cytosine using this method is DeltaH(acid) = 343 +/- 3 kcal mol(-1), PA = 227 +/- 3 kcal mol(-1). We also examined 1-methyl cytosine, which has fewer accessible tautomers than cytosine. We measure a DeltaH(acid) of 349 +/- 3 kcal mol(-1) (DeltaG(acid) = 342 +/- 3 kcal mol(-1)) and a PA of 230 +/- 3 kcal mol(-1) (GB = 223 +/- 3 kcal mol(-1)). Our ultimate goal is to understand the intrinsic reactivity of nucleobases; gas-phase acidic and basic properties are of interest for chemical reasons and also possibly for biological purposes because biological media can be quite nonpolar.     

Molecular structure and antioxidant properties of delphinidin

Density functional theory calculations were performed to evaluate the antioxidant activity of delphinidin, taking into account its acid/base equilibrium. The conformational behavior of both the isolated and the aqueous solvation species (simulated with the polarizable continuum model) were analyzed at the B3LYP/6-31++G(d,p) level, considering the cationic, neutral, and anionic forms, the latter two forms consisting of diverse tautomers. The analysis of their electron density distributions, using the quantum theory of atoms in molecules, reveals several facts that are not in line with their usual Lewis structures. The prototropic preferences observed in the gas phase and in solution are similar. Thus, in both phases, most stable tautomer of neutral delphinidin is obtained by deprotonating the hydroxyl at C4', and the most stable tautomer of the anion is obtained by deprotonating the hydroxyls at C4' and C5. All the planar conformers obtained display an intramolecular hydrogen bond (IHB) between O3 and H6'. Furthermore, the most stable tautomers of the neutral and anionic forms display two IHBs between O4' and H3' and H5'. To obtain ionization potentials (IPs) and homolytic O-H bond dissociation enthalpies (BDEs), the corresponding radical species were optimized at the UB3LYP level. Heterolytic O-H bond dissociation enthalpies (proton dissociation enthalpies, PDEs) were also computed. The expected important antioxidant activity can be justified from these results. IP, O-H BDE, and O-H PDE values suggest that one-step H atom transfer rather than sequential proton loss-electron transfer or electron transfer-proton transfer would be the most favored mechanisms for explaining the antioxidant activity of delphinidin in nonpolar solvents as well as in aqueous solution.     

Five isomers of monomeric cytosine and their interconversions induced by tunable UV laser light

Photoisomerization processes involving five isomers of cytosine were induced by narrowband tunable UV irradiation of matrix-isolated monomers of the compound. Irradiation of an argon matrix containing cytosine monomers with UV λ = 313 nm laser light resulted in syn?anti photoisomerizations between the two imino-oxo forms, whereas the substantially more populated amino-hydroxy and amino-oxo forms stayed intact. Subsequent irradiation with shorter-wavelength UV λ = 311 nm laser light led to two concomitant phototautomeric processes consuming the amino-oxo isomer: (i) an oxo → hydroxy hydrogen-atom transfer photoprocess converting the amino-oxo form into the amino-hydroxy tautomer; (ii) amino → imino hydrogen-atom transfer converting the amino-oxo form into the imino-oxo isomers. The UV-induced phototransformations, together with mutual conversions of the two amino-hydroxy conformers induced by irradiation with narrowband NIR light, allowed positive detection and identification of the five isomeric forms of monomeric cytosine. This is the first experimental observation of all five low-energy isomers of cytosine.     

Effect of the H-bonding on aromaticity of purine tautomers

Four tautomers of purine (1-H, 3-H, 7-H, and 9-H) and their equilibrium H-bonded complexes with F(-) and HF for acidic and basic centers, respectively, were optimized by means of the B3LYP/6-311++G(d,p) level of theory. Purine tautomer stability increases in the following series: 1-H < 3-H < 7-H < 9-H, consistent with increasing aromaticity. Furthermore, the presence of a hydrogen bond with HF does not change this order. For neutral H-bonded complexes, the strongest and the weakest intermolecular interactions occur (-14.12 and -10.49 kcal/mol) for less stable purine tautomers when the proton acceptor is located in the five- and six-membered rings, respectively. For 9-H and 7-H tautomers the order is reversed. The H-bond energy for the imidazole complex with HF amounts to -14.03 kcal/mol; hence, in the latter case, the fusion of imidazole to pyrimidine decreases its basicity. The ionic H-bonds of N(-)···HF type are stronger by ~10 kcal/mol than the neutral N···HF intermolecular interactions. The hydrogen bond N(-)···HF energies in pyrrole and imidazole are -32.28 and -30.03 kcal/mol, respectively, and are substantially stronger than those observed in purine complexes. The aromaticity of each individual ring and of the whole molecule for all tautomers in ionic complexes is very similar to that observed for the anion of purine. This is not the case for neutral complexes and purine as a reference. The N···HF bonds perturb much more the π-electron structure of five-membered rings than that of the six-membered ones. The H-bonding complexes for 7-H and 9-H tautomers are characterized by higher aromaticity and a much lower range of HOMA variability.     

Excited state tautomerization of azaindole

Fluorescent tryptophan analogs, like azatryptophan, offer an advantage for exploring protein and peptide structure and dynamics. The chromophoric moieties, azaindole, of the azatryptophan analogs are investigated for their potential as fluorescent probes. The photophysical properties of 4-azaindole (4AI) and 5-azaindole (5AI) and their tautomers are characterized through computational and experimental methods. Both 4AI and 5AI undergo excited state tautomerization in the presence of 1 M NaOH. The protonated forms of 4AI and 5AI have a fluorescence emission of 415 and 410 nm, respectively, while the tautomers of 4AI and 5AI have a fluorescent emission of 480 and 450 nm, respectively. Gas phase computations (B3LYP/6-31+G**) show that the N1H azaindole tautomer is lower in energy in the ground state by as much as 12.5 kcal mol(-1), while the N(n)H azaindole tautomer is lower in energy in the excited state by as much as 18.1 kcal mol(-1). Solvent effects on the tautomer energy differences were computed using the isodensity polarized continuum model (IPCM). The polarity of the solvent helps to reduce the energy difference between the tautomers in the ground state by as much as 5.8 kcal mol(-1), but not enough to reverse the ground state tautomer preference.     

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.     

Deprotonated cytosine anions: a theoretical prediction of photoelectron spectra

Predictions on the photoelectron spectra of deprotonated cytosine anions (cytosinate, Cye(-)) have been made with ab initio electron propagator methods. Two imino-oxo forms are most stable, but four other isomers have energies within 10 kcal/mol. The first vertical electron detachment energies (VEDEs) for the three most stable Cye(-) isomers are approximately 3.4 eV. Imino-oxy VEDEs are about 0.3 eV smaller. For each anion, the lowest VEDE corresponds to a pi Dyson orbital. The order of higher final states is changed when relaxation and correlation effects are considered. Considerable mixing between lone-pair and bonding lobes occurs in the sigma Dyson orbitals.     

Valence anions in complexes of adenine and 9-methyladenine with formic acid: stabilization by intermolecular proton transfer

Photoelectron spectra of adenine-formic acid (AFA(-)) and 9-methyladenine-formic acid (MAFA(-)) anionic complexes have been recorded with 2.540 eV photons. These spectra reveal broad features with maxima at 1.5-1.4 eV that indicate formation of stable valence anions in the gas phase. The neutral and anionic complexes of adenine/9-methyladenine and formic acid were also studied computationally at the B3LYP, second-order M?ller-Plesset, and coupled-cluster levels of theory with the 6-31++G** and aug-cc-pVDZ basis sets. The neutral complexes form cyclic hydrogen bonds, and the most stable dimers are bound by 17.7 and 16.0 kcal/mol for AFA and MAFA, respectively. The theoretical results indicate that the excess electron in both AFA(-) and MAFA(-) occupies a pi* orbital localized on adenine/9-methyladenine, and the adiabatic stability of the most stable anions amounts to 0.67 and 0.54 eV for AFA(-) and MAFA(-), respectively. The attachment of the excess electron to the complexes induces a barrier-free proton transfer (BFPT) from the carboxylic group of formic acid to a N atom of adenine or 9-methyladenine. As a result, the most stable structures of the anionic complexes can be characterized as neutral radicals of hydrogenated adenine (9-methyladenine) solvated by a deprotonated formic acid. The BFPT to the N atoms of adenine may be biologically relevant because some of these sites are not involved in the Watson-Crick pairing scheme and are easily accessible in the cellular environment. We suggest that valence anions of purines might be as important as those of pyrimidines in the process of DNA damage by low-energy electrons.     

Hydrogen atom and hydride anion addition to adenine: structures and energetics.

The radicals and anions derived from the 9H tautomer of adenine by adding a hydrogen atom to one of the four double bonds of the adenine framework have been studied. Computations were carried out using a carefully calibrated density functional (B3LYP) method and basis set (DZP++). Optimized geometries, energies, and vibrational frequencies are predicted for eight radicals and anions. The radicals are found to lie in a range of 22 kcal mol(-1), with the radical derived by addition to the C(8) carbon atom being the lowest lying energetically. The anions are predicted to be bound species in the gas phase with an energetic range of 43 kcal mol(-1). Anions produced by addition of a hydride ion to adenine carbon atoms are found to be the most favorable. Six of the anions are predicted to be stable species with respect to electron detachment. The adiabatic electron affinities, vertical electron affinities, and vertical detachment energies are computed for the first time. Electron affinities for these radicals range from 0.0 to 2.0 eV. Radicals produced by addition to a nitrogen atom have near-zero adiabatic electron affinities, while radicals produced by addition at carbon atoms have considerably higher electron affinities.     

Stability and aromaticity of tautomers and kinetics of proton transfer in 6-methylpentafulvene and its exo-substituted derivatives: a computational study

Thermodynamic and kinetic aspects of the tautomeric equilibrium of 6-methylpentafulvene and its exo-substituted derivatives were investigated at the B3LYP/6-311 ++G(d,p) level of theory for 17 substituents. It was found that in the case of CF₃ and COCN derivatives, the most stable form is the tautomer in which the proton migrated from the exo-methyl group to a ring carbon atom. The activation energy for such proton transfer is in the range of 53–61 kcal/mol depending on the substituent, NH₂ derivative being an exception with a very high value of 114 kcal/mol. Proton transfers between consecutive ring carbon atoms are associated with much lower activation energies, in general below 30 kcal/mol. The aromaticity of tautomers and transition states of substituted 6-methylpentafulvene was analyzed by employing geometric (HOMA) and electronic (pEDA) indices. It was found that the aromaticity of the nominal form of the molecule is the main driving force behind the stability order of the tautomers. In the case of most substituents, the aromatization of transition states is substantial comparing to the nominal form and is an important factor lowering the activation energy. Solvent effects were modeled by means of PCM and SMD methods.     

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.     

Effects of microsolvation and aqueous solvation on the tautomers of histidine: a computational study on energy, structure and IR spectrum

Microsolvation and combined microsolvation-continuum approaches are employed to investigate the structures and energies of canonical and zwitterionic histidine conformers. The effect of hydration on the relative conformational stability is examined. The strategy of exploring singly and doubly hydrated structures and the possible microsolvation patterns are described. We find that bonding water molecule may significantly change the relative conformational stabilities. In gas phase, the singly and doubly hydrated canonical forms are more stable than their zwitterionic counterparts. In solution, the continuum solvent model shows that bare zwitterionic form is more stable than bare canonical form by 1.1 kcal/mol. This energy separation is increased to 2.2 and 3.4 kcal/mol with inclusion of one and two explicit water molecules, respectively. We have also observed that the doubly hydrated structures obtained by combining two water molecules simultaneously to the solute molecule are preferred over the stepwise hydration. Hydrogen bond energies for the most stable hydrated histidine tautomers are determined by the atoms in molecules theory. The infrared (IR) spectra for the most stable singly and doubly hydrated structures of both histidine tautomers in gas phase are characterized. The stretching frequencies for NH of imidazole ring and OH of COOH are red shifted due to the hydrations. The IR spectra for the most stable zwitterionic tautomers in solution are also presented and discussed in connection with the comparison to the experiments. The pKa values obtained for the ring protonated zwitterions with two explicit water molecules appear to be in good agreement with the experiments.