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ORIGINAL RESEARCH
Can anion interaction accelerate transformation of cytosinetautomers? Detailed view form QTAIM analysis
Marjan Jebeli Javan • Zahra Aliakbar Tehrani •
Alireza Fattahi • Zahra Jamshidi
Received: 7 January 2012 / Accepted: 11 March 2012 / Published online: 30 March 2012
� Springer Science+Business Media, LLC 2012
Abstract The relative stabilities and noncovalent interac-
tions of the six low-lying energy tautomers of cytosine
nucleobase with some biological anions (such as F-, Cl-, and
CN-) have been investigated in gas phase by density func-
tional theory (DFT) method in conjunction with 6-311??G
(d,p) atomic basis set. Furthermore, to systematically inves-
tigate all possible tautomerisms from cytosine induced by
proton transfer, we describe a study of structural tautomer
interconversion in the gas phase and in a continuum solvent
using DFT calculation. We carried out geometrical optimi-
zations with the integral equation formalism of polarizable
continuum (IEF-PCM) model to account for the solvent
effect, and the results were compared with those in the gas
phase. The result of calculation revealed that anions bind
mostly in a bidentate manner via hydrogen bond, and sta-
bilization energies of these complexes are larger than those in
the case when anions bind in a monodentate manner. The
quantum theory of atoms in molecules (QTAIM), natural
bonding orbital (NBO) and energy decomposition analysis
(EDA) have also been applied to understand the nature of
hydrogen bond interactions in these complexes. NBO anal-
ysis reveals that the interaction patterns between the anions
and the tautomers are r-type interaction between lone pairs
and r�N�H
, r�O�H
and r�H�F
antibonding orbitals. Also, according
to these theories, the interactions are found to be partially
electrostatic and partially covalent. EDA results identify that
these bonds have less than 35% covalent character and more
than 65% electrostatic, and the covalent character increases
in different anions in the order F- [ CN- [ Cl-. On the
other hand, orbital interaction energies of complexes of F-
anion are more than those of Cl- and CN- complexes. The
lower orbital interaction energies in complexes of Cl- and
CN-anions imply less charge transfer and stronger ionic
bond character. Furthermore, relationship between the orbital
interaction energy (E2) with hydrogen bonding energy
(EH���X) and the electron density (q(r)) with hydrogen bond-
ing energy of F-, Cl- and CN- complexes have also been
investigated.
Keywords Tautomerization � Anion interaction �Quantum theory of atoms in molecules analysis � Hydrogen
bonding
Introduction
Nucleic acid bases make up the DNA structure and play a
major part in the transmission of the genetic code. They
predominantly occur in the one isomeric form whose
interactions ensure the faithful replication of the code.
However, they can exist in other tautomeric forms (struc-
tures differing in the position of a proton), which could
lead to base-pair mismatching and thus mutations [1, 2].
Tautomerism is a well-known phenomenon occurring in
nucleic acid bases [3–13] in which proton transfer from the
heterocyclic ring nitrogen to an exocyclic oxo- or imino-
group leads to the formation of either an –OH or an –NH2
functionality. These processes are keto-enol or imino-
amino tautomerism, respectively. Tautomerism makes the
ion-molecule behavior of these molecules complex because
there can be several different isomers for each species that
can potentially coexist.
M. Jebeli Javan � Z. A. Tehrani � A. Fattahi (&)
Department of Chemistry, Sharif University of Technology,
P.O. Box 11365-9516, Tehran, Iran
e-mail: [email protected]
Z. Jamshidi
Chemistry and Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran
123
Struct Chem (2012) 23:1843–1855
DOI 10.1007/s11224-012-9993-2
Tautomeric equilibria of pyrimidine bases are of
continuing interest from both theoretical [14–22] and
experimental [23–26] points of view, partly due to sug-
gestions that the presence of unusual tautomers may have
important biological properties, such as mutagenesis. One
hypothesis suggests that the frequency of mispairing in
DNA and thus mutagenesis is correlated with equilibrium
constants for the keto-enol or amino-imino tautomerization
[27, 28], which is strongly sensitive to the interaction of
these molecules with their environment. In addition,
knowing how these tautomerization energies change in
different environments can give an insight into the influ-
ence of environment effects on molecular stability. For
example, presence of metal ions near DNA nucleobases
can strongly affect electron distribution in the bases and
thus these interactions with nitrogen bases can stabilize
different tautomers, modifying the orientation of hydrogen
bonds that are crucial for formation of the double helix
structure [29–40].
Interactions between nucleic acid bases and molecules
or ions in gas phase have been the subject of numerous
studies [41–49]. Furthermore, the interaction of metal ions
with nucleic acid bases is important in biological processes,
and several metal cations (such as Li?, K?, Na?, Ca2?,
Mg2?, etc.) have been extensively studied [50–58]. How-
ever, theoretical investigations on the interaction of anions
with nucleic acid bases are scarce, because the practical
scope for recognition and binding of anions is considerably
narrower than that for cations [59]. One reason for this is
because concentrations of negative potential are more
accessible and manageable on the molecular scale than
concentrations of positive potential.
Various factors such as hydrogen bonding [60], ion–
dipole, ion–ion interactions and Van der Waals interactions
can affect anion complexation. In general, this occurs via
appropriate substituents such as –OH or –NH groups.
However, C–H bonds are also polarized, although to a
lesser extent, and have been found to also be able to par-
ticipate in hydrogen bonding [61]. These groups are able to
make specific hydrogen bond interactions with other mol-
ecules, ranging from small drugs recognized in the minor
groove of DNA (minor-groove binders) to macromolecules
interacting with the major groove. Nevertheless, during the
last two decades, many experimental investigations have
been performed detailing the challenges of designing
receptor molecules involving anions, because of the
potential role these receptor molecules play in vast areas of
biology, medicine, catalysis and environmental science.
For this reason, an abundance of computational studies
have appeared in the literature that consider hydrogen
bonding interactions involving DNA residues. With this in
mind, knowledge of energies of such interactions is
required to understand the determinants of binding affinity
and specificity such as charge–charge interactions and
hydrogen bonding.
In this study,1 we consider detailed computational study
of complexation behavior of cytosine tautomers with
selected biological anions such as fluoride, chloride and
cyanide by means of DFT method with B3LYP/6-311??G
(d,p) orbital basis sets. The geometries, bond energies and
attachment sites of the most stable structures of these
nucleobases complexes have been investigated carefully.
The quantum theory of atoms in molecules (QTAIM),
natural bonding orbital (NBO) and energy decomposition
analysis (EDA) have been applied to interpret the nature of
these interactions. Furthermore, we try to answer a ques-
tion: ‘‘What do anions play in keto$enol or amino$imino
tautomerization of cytosine nucleobase in both gas phase
and solution?’’
This work addresses this question and focuses on the
following aspects: (i) investigation of the proton-transfer
process through all possible pathways and (ii) investigation
of the role of water molecules in the proton-transfer pro-
cess and determination of the origin of the phenomena
induced by water molecules. We have investigated the
proton-transfer process of cytosine (a) in the gas phase and
(b) in a solvent by adopting the integral equation formalism
of polarizable continuum (IEF-PCM) model.
Computational details
Initial search of minima on the potential energy surface for
cytosine tautomers and their complexes with anions of
interest at the relative energy range of 10 kcal/mol was
carried out by MMFF level using Spartan software [62].
These structures were optimized using the DFT in con-
junction with B3LYP/6-311??G (d,p) atomic basis
[63–67]. Energy minimizations followed by harmonic
vibrational calculations were performed at this level of the-
ory. Local minima were verified by establishing that the
matrix of energy second derivatives (Hessian) has only
positive eigenvalues. Transition states between any two
conformers were explored employing the quadratic syn-
chronous transit (QST2) methodology [68]. Energetic bar-
rier for conformational interconversion has been obtained for
all structures of interest using the same method and basis set.
To explore the tautomer interconversion in aqueous solution,
the IEF-PCM model has been used [69]. The EDA was done
using the program package ADF (2009.01) [70–72], which is
based on the work by Ziegler and Rauk [73] and Morokuma
[74]. The bonding analysis was carried out at the B3LYP/
TZ2P level of theory.
1 Presented in spring 2010 meeting of the ACS division of
Carbohydrate Chemistry.
1844 Struct Chem (2012) 23:1843–1855
123
In anion complexation of cytosine tautomers, anion
affinity (AA) was assumed to be the negative of the
enthalpy formation of the following process:
Lþ An� ! L� A½ �n��DH�rxn ¼ AA; ð1Þ
where L represents the cytosine tautomer and An- is anion
of interest. Using the standard thermodynamic figure, we
can write:
DH298 ¼ DE298 þ D pvð Þ ¼ DE298 þ DngRT ¼ DE298 � RT
ð2Þ
AA Lð Þ¼ � DH298¼� DE þ RT ¼ � E L� Að Þn�
þ E Lð Þ þ E An�ð Þ þ RT : ð3Þ
Results and discussion
Relative stabilities of cytosine tautomers
The first part of this article deals with the relative stabilities
of the tautomers. The second section describes the gas
phase interaction between cytosine tautomers with some
biological anions such as F-, Cl- and CN-. It must be
mentioned that the interaction between the canonical form
of cytosine nucleobase and F-, Cl-, CN-, NO3-, SO4
2-
and OH- anions has been investigated in our previous
study [75]. However, in this study, binding energies of the
other tautomers with F-, Cl- and CN- were calculated as
well. In addition, the role of anions in keto$enol or ami-
no$imino tautomerization of cytosine nucleobase in both
gas phase and solution was investigated.
Tautomeric equilibrium of cytosine nucleobase has been
the subject of several experimental [76, 77] and theoretical
[78–82] studies in the gas phase. The keto-amino form (C1
tautomer, see Fig. 1 for more details) is the ‘‘canonical’’
structure of cytosine found in DNA and RNA. It is worth
mentioning that three of the six low-energy tautomers of
isolated cytosine, C2, C3 and C6 tautomers, are not
accessible in DNA and RNA because the ribose would not
migrate. We calculated the relative stability of these tau-
tomers. Absolute energies (E in a.u), relative energies
(DE in kcal/mol), relative free energies (DG in kcal/mol)
and dipole moments (l in Debye) for different tautomeric
forms of cytosine nucleobase are collected in Table 1. The
computation revealed 0.0–22.4 kcal/mol energy disparity
for these tautomers.
In agreement with most of previous studies [83, 84], our
results revealed that C1 is the most stable tautomer in the
gas phase in solid cytosine. The dipole moment of C3
tautomer, 4.94 D, is larger than that of C2 tautomer. This
suggests that if the relative stabilities of cytosine tautomers
could be predicted based solely on their dipole moments,
then C2 would be expected to be more stable than C1 and
C3. The very large dipole moment and the steric repulsion
between the hydrogen atom bound to N3 and the adjacent
amino hydrogen atom result in decreased stability of C6
tautomer and lead to an *2� decrease in the H–N–H angle.
In summary, cytosine tautomers have the following sta-
bility sequence predicted at B3LYP/6-311??G (d,p) level
of theory: C1 [ C2 [ C3 [ C4 [ C5 [ C6.
Unimolecular tautomerization of cytosine nucleobase
In earlier study, Russo et al. [37] investigated relative
stabilities and unimolecular tautomerization processes that
allow interconversion of C1 and C3 cytosine tautomers.
Their calculations were carried out at the B3LYP/6-311?G
(2df, 2p) level of theory. DFT tends to overestimate the
stability of C1 tautomer, and at the level of theory
employed in their study, the relative stabilities of these
tautomers follow the order of C1 \ C3. Their studies also
N
NH
N
O
HaHb
1
4
5
6
2
3
4
NH
N
NH
OH
4
4
6
5
12
3N
N
NH2
OH1
2
3
4
4
5
6
NH
NH
NH
O
1
2
4
5
6
34
N
NH
NH
OH
4
3
2
1
5
6
4 NH
N
NH2
O
4
4
3
21
6
5
C1 C2 C3
C4 C5 C6
Fig. 1 Chemical structures and atom numbering of cytosine tautom-
ers; those investigated in this study
Table 1 B3LYP/6-311??G (d,p) absolute (E in a.u) and relative
energies (DE in kcal/mol) relative free energies (DG in kcal/mol) and
dipole moments (l in Debye) at 298 K for different tautomeric forms
of cytosine
Tautomer E DE0 DE298 DG298 l
C1 -395.053158 0.0 0.0 0.0 6.75
C2 -395.051713 1.2 1.0 1.4 3.47
C3 -395.050680 2.1 1.9 2.3 4.94
C4 -395.041920 6.9 6.9 7.0 8.25
C5 -395.031194 14.2 13.9 14.6 1.84
C6 -395.017648 22.4 22.2 22.5 5.65
Struct Chem (2012) 23:1843–1855 1845
123
found that the barriers for the C1$C3 unimolecular tau-
tomerization processes are too large (37.40 kcal/mol) to be
overcome by thermal vaporization. In this study, we rein-
vestigated these tautomerization processes and extended
our studies to include unimolecular tautomerization pro-
cesses involving C2, C3, C4 and C5 tautomers.
Rodgers et al. [12] suggested that there are five direct
unimolecular tautomerization processes that allow inter-
conversion of six tautomers of cytosine via simple proton
transfer. These unimolecular tautomerization processes can
be divided into three groups: 1, 2 proton transfer, cis–trans
isomerization and r-bond rotation. The tautomerization
processes that we investigated in this study belong to 1, 2
proton transfer group between adjacent atoms. The
C1$C3 and C4$C5 transformations correspond to sim-
ple keto-enol tautomerization, whereas C2$C3 and
C4$C1 interconversion correspond to an amino-imino
tautomerization. During these unimolecular tautomeriza-
tion processes, an r-bond is broken and a new r-bond is
formed. The potential energy profile for unimolecular
tautomerization process of isolated tautomers of cytosine
nucloebase in gas phase is shown in Fig. 2. As a result,
these processes demonstrate very large activation energy
barriers, 34.2 kcal/mol (C1 ? C3 transformation),
28.1 kcal/mol (C5 ? C4 transformation), 45.1 kcal/mol
(C3 ? C2 transformation) and 37.8 kcal/mol (C4 ? C1
transformation), respectively.
Anion interactions of cytosine tautomers
Based on our results, the electrostatic and polarization
interactions between anions and neutral molecule deter-
mine the possible attachment sites and the geometry of
adducts. Initial structures were determined by placing
anion around tautomers in ‘‘chemically intuitive’’ positions
where the interaction with polar hydrogen atoms (N–H���X,
C–H���X and O–H���X; X = F-, Cl- and CN-) of cytosine
tautomers was a possibility. Optimized structure and main
geometrical parameters of the most stable complexes of
cytosine tautomers with anions of interest calculated at
B3LYP/6-311??G (d,p) level of theory are shown in
Fig. 3. Furthermore, B3LYP/6-311??G (d,p) absolute
E (in a.u), relative energies (DE in kcal/mol), relative free
energies (DG in kcal/mol), dipole moments (l in debye)
and anion affinity at 298 K (DHAA in kcal/mol) for dif-
ferent complexes of cytosine tautomers with anions are
given in Table 2. As shown in Fig. 3, interaction patterns
depend on anionic species and types of tautomers. In these
complexes, interactions are completely through hydrogen
bonding, which causes elongation of N/O–H bond in tau-
tomeric ligand and thereby lower associated N/O–H bond
orders. Results of calculations revealed two possible
geometries for these complexes: uni-core interaction with a
single hydrogen bond and bifurcated interaction with two
hydrogen bonds. It is worth mentioning that the fluoride
anion separates a hydrogen atom from N/O–H bonds of
cytosine tautomers during optimization process, although
the chloride and cyanide anions only weaken and elongate
these bonds. For instance, during interaction of fluoride
anion with C1 tautomer, deprotonation of N1–H1 bond
occurs during geometry optimization process of the com-
plex of C1 tautomer with fluoride anion. Then, the
hydrogen bond is formed between N1 anion and hydrogen
fluoride (H–F) molecule. The H–F bond distance is
1.026 A, a little longer than the bond distance of gas phase
HF molecule (0.922 A). The bond length for this
Fig. 2 Potential energy profile
for the unimolecular
tautomerization of the isolated
tautomers of cytosine at 298 K
in the gas phase calculated at
B3LYP/6-311??G (d,p) level
of theory
1846 Struct Chem (2012) 23:1843–1855
123
Fig. 3 B3LYP/6-311??G (d,p) optimized structures of complexes of cytosine tautomers with anions of interest. Distances are in angstrom (A)
Struct Chem (2012) 23:1843–1855 1847
123
intermolecular H bond is 1.496 A. In addition, it is also
observed that the H–F molecule is in the same plane with
C1 anion. In the C1–Cl complex, chloride anion is placed
near the N4–Hb and C5–H5 bonds. Also, as expected,
formation of Cl���Hb–N4 and Cl���H5–C5 hydrogen bonds
lengthen associated N4–Hb and C5–H5 bonds by 0.035 and
0.002 A, respectively, thus weakens these bonds. Bond
lengths for these hydrogen bonds are more than that for
C1–F complex. These results show that the hydrogen bond
in C1–F complex should be stronger than that in C1–Cl
complex. The chloride anion remains in the same plane
with the C1 tautomer. In the case of C1–CN complex, the
bond length of N1–H1���CN hydrogen bond is 1.806 A.
In summary, results of calculations revealed that among
complexes of fluoride anion with cytosine tautomers, C6–F
complex is the most stable one. As seen from Table 2,
C2–F complex is found to be the next most stable complex,
lying only 1.9 kcal/mol higher in energy than C6–F com-
plex. The C1–F complex is found to be the next most stable
gas phase complex, lying 3.8 kcal/mol higher in energy
than C6–F complex. Our computational result predicted the
following stability order for complexes of fluoride anion
Table 2 BLYP/6-311??G
(d,p) absolute (E in a.u) and
relative energies (DE in kcal/
mol), relative free energies
(DG in kcal/mol), dipole
moments (l in debye) and anion
affinity at 298 K (DHAA in kcal/
mol) for different complexes of
cytosine tautomers with anions
Complex E DE0 DE298 DG298 DHAA l
C1–F -495.0157838 3.8 3.9 4.1 47.8 9.00
C2–F -495.019705 1.9 1.8 2.3 62.6 5.18
C3–F -495.01508 4.5 4.6 22.9 48.1 8.84
C4–F -494.988212 22.5 22.6 14.9 31.0 10.47
C5–F -495.002633 11.4 11.3 11.9 63.8 7.18
C6–F -495.022006 0.0 0.0 0.0 58.6 0.87
C1–Cl -855.398005 0.0 0.0 0.0 25.7 8.32
C2–Cl -855.382131 9.5 9.2 10.3 30.4 8.55
C3–Cl -855.392355 3.7 3.6 3.7 23.1 10.36
C4–Cl -855.395805 1.5 1.4 1.6 26.2 9.33
C5–Cl -855.374684 14.3 14.1 14.9 33.8 6.66
C6–Cl -855.394257 1.7 1.8 1.3 30.8 5.56
C1–CN -487.978455 3.3 3.8 2.7 22.4 14.46
C2–CN -487.944916 23.6 23.8 23.4 16.3 13.44
C3–CN -487.978187 3.7 4.1 2.9 23.1 11.69
C4–CN -487.982346 1.0 1.4 0.5 26.7 10.99
C5–CN -487.953738 18.5 18.8 18.1 29.6 7.88
C6–CN -487.983117 0.0 0.0 0.0 33.1 11.42
Table 3 Solvent effect for the
transformation of cytosine
tautomers and their complexes
with anions. Energies are given
as kcal/mol, T = 298 K
a Calculated activation
parameters and dipole moments
(l in debye) for the reaction in
gas phaseb Calculated activation
parameters and dipole moments
(l in debye) for the reaction in
aqueous phase using IEF-PCM
model
Structure DEa# DGa
# la DEb# DGb
# lb
C1 6.75 9.64
TS1,3 34.2 34.1 5.85 39.2 39.4 8.06
C1–Cl 8.32 11.97
TS1,3 33.5 33.9 8.1 39.1 39.4 11.31
C3 3.47 4.92
TS3,2 45.1 45.4 1.7 48.3 49.2 2.2
C3–F 8.84 14.76
TS3,2 36.5 36.6 7.07 44.8 44.5 10.79
C4 4.94 6.63
TS4,1 37.8 37.9 5.85 37.9 38 7.92
C4–CN 10.99 15.74
TS4,1 39.6 38.9 12.82 38.3 38.2 18.82
C5 5.65 8.31
TS5,4 28.1 28.4 5.97 29.7 30 8.21
C5–CN 7.88 10.1
TS5,4 27.8 27.1 9.62 28.9 28.9 12.71
1848 Struct Chem (2012) 23:1843–1855
123
with cytosine tautomers: C6–F [ C2–F [ C1–F [ C3–
F [ C5–F [ C4–F. Furthermore, for complexes of cyto-
sine tautomers with chloride anion the following stability
order is observed: C1–Cl [ C4–Cl [ C6–Cl [ C3–
Cl [ C2–Cl [ C5–Cl (see Table 2 for more details). In the
case of cyanide anion, relative stability of complexes of
cytosine tautomers with this anion is C6–CN [ C4–
CN [ C1–CN [ C3–CN [ C5–CN [ C2–CN. These
trends indicate that in the presence of anions (F-, Cl- and
CN-), the order of relative energies of the six cytosine
tautomers has been changed (see Table 2 for more details).
Unimolecular tautomerization of complexes of cytosine
tautomers with anions of interest
In this section, we try to answer a question: ‘‘What do
anions play in keto$enol or amino$imino tautomeriza-
tion of cytosine nucleobase?’’ The intramolecular proton
transfers occurring in F-–cytosine, Cl-–cytosine and
CN-–cytosine are characterized through the analysis of the
energy profiles (see Fig. 4). Information about the mech-
anism of proton transfer is obtained through simultaneous
analysis of the evolution along reaction coordinate of few
key structural and electronic properties. This information
together with characterization of transition states allows
one to identify the properties that are activated or inhibited
along the reaction coordinate; thus, defining processes that
are driving the reaction. As shown in Fig. 4, activation
energy barrier for C3–F ? C2–F transformation is calcu-
lated to be 36.5 kcal/mol. This activation energy barrier is
8.6 kcal/mol less than that in C3 ? C2 transformation
(45.1 kcal/mol). This result revealed that the presence of
fluoride anion near O2–H atom of C3 tautomers accelerates
tautomerization transformation via proton-transfer reac-
tion. However, as shown in Fig. 4, for chloride and cyanide
anions, activation energy barriers are lower than that of in
fluoride anion. For instance, in the case of Cl- anion,
activation energy barrier for C1–Cl ? C3–Cl transfor-
mation is 33.5 kcal/mol. Also, for CN- anion, these values
in C5–CN ? C4–CN and C4–CN ? C1–CN transfor-
mations are 27.8 and 39.6 kcal/mol, respectively. These
results show that formation of hydrogen bonds in the
complexes of cytosine tautomers with anions facilitates
tautomerization processes.
The proton-transfer process in a solvent (IEF-PCM
model)
In fact, many structural features that are necessary for the
biological functions of nucleic acids depend on the inter-
actions with surrounding water. For this reason, we also
investigated the role of water in the tautomerism process.
We use this method to deal with this problem: investigation
of proton-transfer in a cavity surrounded by a continuum
solvent (water); IEF-PCM model was used. It is evident that
various tautomers have quite different dipole moments,
presented in Table 3. For instance, in the case of cytosine
tautomers, the smallest one belongs to C3 and the biggest
one belongs to C1. It is known that in the case of F- and Cl-
anions, a larger value of the dipole moment indicates more
stabilization when the complex is exposed to a polar solvent
such as water. Hence, we can predict that cytosine tautomers
and their complexes with these anions become much more
stable, whereas the transition states will become less stable
in solvent surroundings. As we can see from Table 3 (part
C), when we compared with the results calculated in the gas
Fig. 4 Potential energy profile for unimolecular tautomerization of
complexes of cytosine tautomers with selected anions in the gas phase
Struct Chem (2012) 23:1843–1855 1849
123
phase (Table 3, part B), solvent has different effects on the
stabilities of the structures. The existence of solvent
increases the stability of cytosine tautomers and their
complexes with F- and Cl- anions; on the other hand, it
decreases the stability of transition states. Therefore, solvent
increases the transformation barrier from one tautomer to
another. In the case of CN-, the existence of solvent
increases the stability of C5–CN more than TS5,4; therefore,
solvent increases the barrier from C5–CN to C4–CN. On the
other hand, it decreases the barrier from C4–CN to C1–CN
by 1.3 kcal/mol. As shown in Table 3, the larger value of
the dipole moment for TS4,1 indicates more stabilization of
this structure than C4–CN when the complex is exposed to a
polar solvent such as water.
Natural bonding orbital analysis
NBOs provide the most accurate possible (natural Lewis
structure) picture of the wavefunction w because all the
orbital details are mathematically chosen to include the
highest possible percentage of the electron density. A
useful aspect of the NBO method is that it provides
information about the interactions in both filled and virtual
orbital spaces that facilitates the analysis of intra- and
inter-molecular interactions. A second-order perturbation
theory analysis of the Fock matrix was carried out to
evaluate the donor–acceptor interaction in the NBO basis
[85]. In this analysis, the stabilization energy E2 related to
the delocalization trend of electrons from donor to acceptor
orbitals was calculated via perturbation theory. If this
energy between a donor bonding orbital and an acceptor
orbital is large, then there is a strong interaction between
them. For each donor orbital (i) and acceptor orbital (j), the
stabilization energy E2 is associated with i ? j delocal-
ization, given by the following equation:
E2 ¼ DEij ¼ �nrrjFjr�h i2
er� � er¼ �nr
F2ij
De;
where Fij is the Foch matrix element between the NBO i(r)
and j(r*), er and r* are the energies of r and r* NBOs and
nr is the population [85].
Calculated second-order interaction energies (E2)
between donor and acceptor orbitals of hydrogen bond for
complexes of cytosine tautomers with anions of interest are
given in Table 4. NBO analysis reveals that the interaction
patterns between the anions and tautomers are r-type
interaction between lone pairs and r�N�H, r�O�H and r�H�F
antibonding orbitals. As seen in Table 3 for complexes of
F- anion with cytosine tautomers, the greatest delocaliza-
tion interaction occurs through one of the O2, N4 and N1
lone pairs to r�H�F antibonding orbital (i.e., nO2 ! r�H2�F,
nN4 ! r�Hb�F and nN1 ! r�H1�F) rather than the expected
nF ! r�H2�O2=r�Hb�N4=r
�H1�N1. These results suggest that
O2–H2, N4–Hb and N1–H1 bonds have been removed and
H–F covalent bond has been formed via interaction of F-
anion with O2–H2, N4–Hb and N1–H1 bonds in tautomers.
The orbital interaction energies of these complexes vary
from 60.5 to 141.2 kcal/mol (see Table 4 for more details).
Additionally, the strong nO2 ! r�H2�F, nN4 ! r�Hb�F and
nN1 ! r�H1�F interactions indicate that the charge transfer
is mainly due to formation of H–F covalent bond. As for
complexes of Cl- anion, the delocalization interaction
occurs from the Cl- lone pairs to r�O2�H2, r�N4�Hb, r�N1�H1
and r�N3�H3 antibonding orbitals. Their orbital interaction
energies vary from 23.3 to 56.3 kcal/mol.
The lower orbital interaction energies for complexes of
chloride anion than that of fluoride anion imply less charge
transfer and stronger ionic bond between Cl- anion and
cytosine tautomers. In the case of complexes of CN- anion,
the orbital interaction energies vary from 25.4 to 65.3 kcal/
mol. Table 3 shows that the greatest orbital interaction is
from N lone pairs in CN to r�N3�H3 in the C2–CN complex,
indicating that the electron transfer from CN- anion to C2
tautomer occurs mainly via r-type interaction with r�N3�H3.
The greatest charge transfers for the orbital interaction
energies in complexes of cytosine tautomer with anions of
interest are observed in the C5–F, C2–Cl and C2–CN
Table 4 Main NBO second-order stabilization energies (E2 in kcal/
mol) calculated at B3LYP/6-311??G (d,p) level of theory for
complexes of cytosine tautomers with anions of interest
Complex Charge transfer type E2
C1–F nN1 ! r�H1�F 70.20
C2–F nO2 ! r�H2�F 72.72
C3–F nO2 ! r�H2�F 60.57
C4–F nN3 ! r�H3�F 47.16
C5–F nO2 ! r�H2�F 141.24
nF ! r�N1�H1 5.30
C6–F nN4 ! r�Hb�F 78.92
C1–Cl nCl ! r�N4�Hb 23.34
C2–Cl nCl ! r�O2�H2 47.60
nCl ! r�N3�H3 8.68
C3–Cl nCl ! r�N4�Hb 24.94
C4–Cl nCl ! r�N1�H1 26.02
C5–Cl nCl ! r�O2�H2 22.39
nCl ! r�N1�H1 20.54
C6–Cl nCl ! r�N4�Hb 38.10
C1–CN nCN ! r�N1�H1 25.45
C2–CN nCN ! r�H3�N3 65.34
C3–CN nCN ! r�N4�Hb 34.82
C4–CN nCN ! r�N1�H1 39.26
C5–CN nCN ! r�N1�H1 54.29
C6–CN nCN ! r�N4�Hb 37.16
1850 Struct Chem (2012) 23:1843–1855
123
Table 5 EDA of cytosine
tautomers with anions of
interest (in kcal/mol)
Complex DEpauli DEelect DEorb DEint
C1–F 123.97 -98.45 (42.7%) -132.05 (57.3%) -106.53
C2–F 111.1 -95.48 (41.1%) -136.75 (58.9%) -121.13
C3–F 8.42 -43.17 (65.5%) -22.73 (34.5%) -57.48
C4–F 106.04 -116.33 (53.6%) -100.64 (46.4%) -110.93
C5–F 116.66 -107.30 (45.6%) -127.80 (54.4%) -118.44
C6–F 32.45 -37.49 (53.3%) -32.84 (46.7%) -37.88
C1–Cl 17.79 -30.24(63.7%) -17.21(36.3%) -29.66
C2–Cl 17.14 -27.41 (62.1%) -16.73 (37.9%) -27
C3–Cl 33.4 -48.42 (62.1%) -29.57 (37.9%) -44.59
C4–Cl 31.06 -53.47 (66.2%) -27.28 (33.8%) -49.69
C5–Cl 21.55 -36.37 (63.9%) -20.52 (36.1%) -35.34
C6–Cl 19.02 -31.98 (64.1%) -17.94 (35.9%) -30.9
C1–CN 21.95 -32.03 (62.0%) -19.59 (38.0%) -29.67
C2–CN 23.29 -33.12 (61.5%) -20.70 (38.5%) -30.53
C3–CN 37.2 -31.67 (50.0%) -31.66 (50.0%) -26.13
C4–CN 33.54 -42.84 (59.5%) -29.20 (40.5%) -38.5
C5–CN 29.15 -43.97 (64.0%) -24.77 (36.0%) -39.59
C6–CN 27.48 -38.06 (61.3%) -24.01 (38.7%) -34.59
Table 6 Bond critical points data for complexes of cytosine tautomers with anions of interest
Complex BCP q(r) r2q(r) G(r) V(r) H(r) –G(r)/V(r) EH���X
C1–F F–H1���N1 0.094 0.064 0.058 -0.100 -0.042 0.580 31.4
C2–F F–H2���O2 0.093 0.149 0.073 -0.110 -0.036 0.669 34.5
C3–F F–H2���O2 0.082 0.160 0.066 -0.093 -0.026 0.716 29.1
C4–F F–H3���N3 0.070 0.097 0.047 -0.630 -0.023 0.675 21.8
C5–F F���H1–N1 0.022 0.087 0.020 0.002 -0.018 1.097 5.7
F–H2���O2 0.148 -0.088 0.091 -0.205 -0.113 0.446 64.2
C6–F F–Hb���N4 0.096 0.065 0.060 -0.103 -0.043 0.578 32.4
C1–Cl Cl���H5–C5 0.008 0.024 0.005 -0.004 0.001 1.295 1.2
Cl���Hb–N4 0.032 0.069 0.019 -0.022 -0.002 0.897 6.8
C2–Cl Cl���H3–N3 0.019 0.055 0.012 0.002 -0.010 1.161 3.3
Cl���H2–O2 0.051 0.064 0.029 -0.042 -0.013 0.688 13.3
C3–Cl Cl���H5–C5 0.006 0.016 0.003 0.001 -0.002 1.286 0.8
Cl���Hb–N4 0.033 0.069 0.020 -0.023 -0.003 0.879 7.2
C4–C1 Cl���H1–N1 0.034 0.070 0.020 -0.003 -0.023 0.879 7.2
C5–C1 Cl���H2–O2 0.034 0.067 0.020 -0.003 -0.020 0.856 7.4
Cl���H1–N1 0.031 0.073 0.020 -0.02 -0.002 0.926 6.7
C6–Cl Cl���Hb–N4 0.042 0.070 0.025 -0.007 -0.030 0.774 10.0
C1–CN CN���H1–N1 0.041 0.102 0.029 -0.026 -0.004 1.888 10.3
C2–CN CN���H3–N3 0.069 0.085 0.044 -0.023 -0.068 1.657 21.2
C3–CN CN���Hb–N4 0.046 0.104 0.033 -0.007 -0.040 1.824 12.5
C4–CN CN���H1–N1 0.052 0.104 0.036 -0.010 -0.047 1.779 14.6
C5–CN CN���H1–N1 0.063 0.098 0.043 -0.061 -0.018 1.701 19.1
C6–CN CN���H3–N3 0.010 0.031 0.006 -0.005 0.001 2.248 1.6
CN���Ha–N4 0.052 0.106 0.037 -0.047 -0.010 1.784 14.7
Struct Chem (2012) 23:1843–1855 1851
123
complexes (see Table 4 for more details). The E2 magni-
tude of the nO2 ! r�H2�F transferences in C5–F complex is
higher than that of nF ! r�N1�H1. Consequently, the nO2 !r�H2�F delocalization interaction stabilizes the hydrogen
bonding of O2���H2–F more than that of in the F���H1–N1
hydrogen bond. These results show that O2���H2–F
hydrogen bond is stronger than F���H1–N1 hydrogen bond.
Due to the larger distances between donor (F atom) and
acceptor (H1–N1 bond), the hydrogen bond in this region is
weaker than that in the region between the H2–F and O2
atom.
It is well known that short hydrogen bonds occur when
the distance between the heteroatoms is less than the sum
of the van der Waals radii (effective radius for closest
molecular packing). The E2 magnitude of the nCl !r�O2�H2 transfer in the C2–Cl complex is more than that of
nCl ! r�N3�H3. Accordingly, the nCl ! r�O2�H2 delocaliza-
tion stabilizes the hydrogen bonding of Cl���H2–O2 more
than the nCl ! r�N3�H3 delocalization in the Cl���H3–N3
hydrogen bond. Thus, these results indicate that Cl���H2–
O2 hydrogen bond is stronger than Cl���H3–N3. In the
C2–CN complex, the hydrogen bond is formed via nCN !r�N3�H3 charge transfer. The E2 magnitude of the nCl !r�O2�H2 charge transfer in C2–Cl complex is lower than that
of nO2 ! r�H2�F and nCN ! r�N3�H3 charge transfers in
C5–F and C2–CN complexes, respectively. Thus, the
Cl���O2–H2 hydrogen bond in C2–Cl complex is weaker
than O2���H2–F and CN���H3–N3 hydrogen bonds in C5–F
and C2–CN complexes, respectively.
Energy decomposition analysis
The interaction of F-, Cl- and CN- with cytosine tauo-
tomers in complexes has been investigated by means of
EDA [73, 74]. In this method, the interaction energy
between two fragments, DEint, is split up into three phys-
ically meaningful components:
DEint ¼ DEPauli þ DEelstat þ DEorb:
DEelstat gives the electrostatic interaction energy
between the fragments, which is calculated with a frozen
electron density distribution in the geometry of the
complex. It can be considered as an estimate of the
electrostatic contribution to the binding energy. DEPauli
gives the repulsive four-electron interactions between
occupied orbitals. In addition, the stabilizing orbital
interaction term DEorb is calculated in the final step of
the analysis when the Kohn–Sham orbitals relax to their
optimal form. The orbital term DEorb can be considered as
an estimate of the covalent contributions to the attractive
interactions. Table 5 collects the results of the EDA
calculations at the B3LYP/TZ2P level for the complexes
of anions with cytosine tautomers. Table 5 also shows the
percentage values of DEelstat and DEorb in the complexes.
The interactions of anions with cytosine tautomers are
mostly electrostatic in nature because the contribution of
the electrostatic term (DEelstat) to the binding energy is
always larger than that of the covalent term (DEorb). The
B3LYP calculations revealed that DEelstat accounts for
41.1–66.2 % of the attractive interactions of anion bonds
with cytosine tautomers. The covalent character of these
bonds increases in the order of F- [ CN- [ Cl-.
Quantum theory of atoms in molecules analysis
In this article, we calculated the electron density topological
properties of our systems using the AIM2000 program [86].
Values of electron densities (q(r), e/a.u3), theirs Laplacians
Fig. 5 Plots of q(r) and EH���X correlation for complexes of cytosine
tautomers with fluoride (a), E(H���X) = 0.001 q(r) ? 0.033, chloride
(b), E(H���X) = 0.003 q(r) ? 0.009 and cyanide (c), E(H���X) = 0.002
q(r) ? 0.013
1852 Struct Chem (2012) 23:1843–1855
123
(r2q(r), e/a.u5), kinetic energy densities G(r), potential
energy densities V(r), electronic energy densities H(r),
hydrogen bond energies (EH���X, kcal/mol) and -G(r)/
V(r) ratio at bond critical points for complexes of cytosine
tautomers with anions of interest are give in Table 6. As
seen from this table, all of hydrogen bonds in complexes of
cytosine tautomers have positive values for r2q(r) (except
F–H2���O2 hydrogen bond in C5–F complex) and negative
values for H(r) (except C5–H5���Cl and N3–H3���N–C
hydrogen bonds in C1–Cl and C6–CN complexes, respec-
tively). Therefore, these hydrogen bonds have partially
covalent character (strong hydrogen bond). Furthermore, as
seen in Table 6, the highest hydrogen bond energies (EH���X)
for cytosine tautomers with F-, Cl- and CN- belong to C5–
F (EH���X = 64.2 kcal/mol), C2–CN (EH���X = 21.2 kcal/
mol) and C2–Cl (EH���X = 13.3 kcal/mol).
In C5–F complex, the magnitude of O2���H2–F
hydrogen bond energy (EH���X) is more than this value for
F���H1–N1 (64.2 and 5.7 kcal/mol, respectively). Thus, the
O2���H2–F H bond is stronger than F���H1–N1 H bond. This
result is in agreement with results of orbital interaction
energies (E2) for these hydrogen bonds (see Table 4). The
similar agreement is also seen between results of NBO and
QTAIM analysis for C2–Cl complex. The amount of
Cl���H2–O2 hydrogen bond energy in the C2–Cl complex
is more than that in Cl���H3–N3 hydrogen bond (13.3 and
3.3 kcal/mol, respectively). Thus, Cl���H2–O2 H bond is
stronger than the Cl���H3–N3 hydrogen bond. As seen from
Table 6, the amount of EH���X in C2–Cl complex is lower
than those in C5–F and C2–CN complexes. Thus, the
Cl���H2–O2 hydrogen bond in C2–Cl complex is weaker
than O2���H2–F and CN���H3–N3 hydrogen bonds in C5–F
and C2–CN complexes, respectively.
Due to the fact that value of q(r) is responsible for the
strength of hydrogen bond, the relationship between
q(r) and EH���X parameters was investigated and plots of
this correlation are illustrated in Fig. 5. As seen in Fig. 5,
EH���X linearly depends on q(r). Furthermore, the relation-
ship between E2 and EH���X was also investigated because
E2 is also responsible for the strength of hydrogen bond,
and the E2 * EH���X correlation plots for complexes of
cytosine tautomers with F- (6a), Cl- (6b) and CN- (6c)
anions were plotted in Fig. 6. As shown in Fig. 6, EH���Xlinearly depends on E2.
Conclusions
A detailed computational study concerning complexes
formed by the interaction of some biochemically important
anions (such as F-, Cl- and CN-) with cytosine tautomers
has been investigated by means of the B3LYP/6-
311??G(d,p) method. Furthermore, to systematically
explore the proton-transfer process of cytosine as well as
the roles water molecules play in these processes, some of
the possible proton-transfer processes of cytosine tautom-
ers in both free and complexed with anions of interest have
been investigated in solution phase. In these complexes,
anions of interest could serve as nonconventional proton
acceptors and nonconventional hydrogen bonds could be
formed, playing a significant role in stabilizing of com-
plexes. The nature of hydrogen bonds was analyzed
through natural bonding orbital (NBO) and quantum theory
atoms in molecules (QTAIM) analysis. It is worth men-
tioning that the presence of anions near these molecules
Fig. 6 Plots of E2 * EH���X correlation for complexes of cytosine
tautomers with fluoride (a), E2 = 0.446 EH���X ? 0.562, chloride (b),
E2 = 0.243 EH���X ? 1.297 and cyanide (c), E2 = 0.278 EH���X ?
3.523
Struct Chem (2012) 23:1843–1855 1853
123
strongly affects electronic distribution in cytosine tautom-
ers. In other words, effect of the anions can favor the
formation of the rare tautomers, which are believed to be
involved in various biochemical processes including point
mutation. Results of calculations can be outlined as
follows:
1. Relative stabilities of complexes of cytosine tautomers
with F-, Cl- and CN- anions have the following order:
C6–F [C2–F[C1–F[C3–F [C5–F[C4–F; C1–
Cl [C4–Cl[ C6–Cl[ C3–Cl[C2–Cl [C5–Cl and
C6–CN [C4–CN [C1–CN [C3–CN[ C5–CN[C2–CN, respectively.
2. The barriers to unimolecular tautomerization for the
C1 ? C3, C5 ? C4, C3 ? C2 and C4 ? C1 tau-
tomerization processes are too large to be overcome by
thermal vaporization. However, formation of hydrogen
bonds in the complexes of cytosine tautomers with
anions facilitate the tautomerization processes, C3–
F ? C2–F, C1–Cl ? C3–Cl and C5–CN ? C4–
CN ? C1–CN and thus provide an energetically
accessible mechanism for the formation C2–F, C3–
Cl and C1–CN.
3. IEF-PCM model indicated that in the presence of water
solvent, proton-transfer processes of cytosine tautom-
ers in both free and complexed with F-, CN- and Cl-
anions become energetically less favorable.
4. NBO analysis revealed that the interaction patterns
between the anions and the tautomers are r-type
interaction between lone pairs and r�N�H, r�O�H and
r�H�F antibonding orbitals. The orbital interaction
energies (E2) of F- complexes cytosine tautomers
are more than those of Cl- and CN- complexes.
5. EDA decomposed the binding energy into three major
components (DEPauli, DEelstat and DEorb). This calcu-
lation indicated that the attractive interaction of
anions-cytosine tautomers’ bonds comes from both
electrostatic and covalent parts. The electrostatic
contribution in most cases is almost two times larger
([65%) in magnitude than the covalent contribution
(\35%). Therefore, the interactions are more electro-
static than covalent, and for different complexes, the
covalent character increases in the order of F- [CN- [ Cl-.
6. Correlation between the electron density (q(r)) and
hydrogen bonding energies (EH���X) for complexes of
F-, Cl- and CN- anions with cytosine tautomers was
investigated. Our results indicated that EH���X is
linearly correlated with q(r).
7. Results of calculation demonstrated that orbital inter-
action energies (E2) responsible for the strength of
hydrogen bonds are linearly correlated with hydrogen
bonding energies (EH���X).
From this study, a greater understanding of hydrogen
bonding interactions involving DNA and RNA molecules
will be obtained. These interactions could provide insight
to an unrecognized control element in biological processes,
providing new and intriguing opportunities of exploring the
electrostatic effects on biological processes.
Acknowledgments Support from Sharif University of Technology
is gratefully acknowledged.
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