Journal of Molecular Structure 1128 (2017) 13e20

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Journal of Molecular Structure

journal homepage: http://www.elsevier.com/locate/molstruc

Characterization of p-stacking interactions between aromatic amino

acids and quercetagetin
Farideh Badichi Akher, Ali Ebrahimi*, Najmeh Mostafavi
Department of Chemistry, Computational Quantum Chemistry Laboratory, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran

a r t i c l e i n f o a b s t r a c t

Article history: In the present study, the p-stacking interactions between quercetagetin (QUE), which is one of the most
Received 13 June 2016 representative flavonol compounds with biological and chemical activities, and some aromatic amino
Received in revised form acid (AA) residues has been investigated by the quantum mechanical calculations. The trend in the
1 August 2016
absolute value of stacking interaction energy jDEj with respect to AAs is HIS > PHE > TYR > TPR. The
Accepted 15 August 2016 P
results show that the sum of donor-acceptor interaction energy between AAs and QUE ( E2) and the
Available online 18 August 2016 P P
sum of electron densities r calculated at BCPs and CCPs between the rings ( rBCPs and rCCP) can be
useful descriptors for prediction of the DE values of the complexes. The OeH bond dissociation enthalpy
Keywords:
Quercetagetin
(BDE) slightly decreases by the p-stacking interaction, which confirms the positive effect of that inter-
Flavonoid action on the antioxidant activity of QUE. A reverse trend is observed for BDE when is compared with the
p-Stacking jDEj values. A reliable relationship is also observed between the Muliken spin density (MSD) distributions
Antioxidant of the radical species and the most convenient OeH bond dissociations. In addition, reactivity is in good
OH BDE correlation with the antioxidant activity of the complexes.
© 2016 Elsevier B.V. All rights reserved.

1. Introduction biology [13e18]. Many theoretical and empirical studies have

Flavonoids are polyphenolic compounds that are present in
fruits, vegetables, coffee beans, green and black tea, red and white
win, herbs and propolis [1]. They have a special importance in the
medical and biological sciences due to their biological activities, e.g.
antiallergic, antioxidant, antiviral, antibacterial and anticancer
[2e4]. Three major subfamilies of flavonoids are flavones, flavonols
and flavanones. The chemical structure of flavonoid is based on
C6eC3eC6 carbon framework (subscripts 3 and 6 represent the
number of carbon in each ring), consisting of two aromatic benzene
rings (rings A and B) linked via an oxygen-containing pyran ring
(ring C) [5,3]. There are differences in the degree of pyran ring
saturation, in the placement of ring B at the C2 or C3 positions of
ring C and the position and the number of hydroxyl groups [3].
Several studies have shown that flavonoids are enzyme inhibitors
and are bound to active sites via noncovalent interactions [6e12].
Noncovalent interactions (hydrogen bond, van der Waals,
charge transfer, p-stacking, etc.) play significant roles in drug
design, supramolecular chemistry, materials science and molecular
* Corresponding author.
E-mail address: ebrahimi@chem.usb.ac.ir (A. Ebrahimi).
focused on p-stacking interactions because of their biological
importance [19e34], especially in the protein-ligand complexes.
There is a set of small and large molecules, including aromatic rings,
which make such biologically important complexes via p-stacking
interactions with aromatic amino acids (AAs) like tryptophan (TRP),
tyrosine (TYR), phenylalanine (PHE) and histidine (HIS) [35e39].
The crystal structures also indicate p-stacking interactions between
ligands and aromatic AAs in the active sites of enzymes. The T-
shaped, edge-to-face, and parallel-displaced stacking configura-
tions are favored energetically in comparison with the sandwich
configuration. It should be noted that the parallel displaced
configuration is observed more frequently than the T-shaped
configuration in the protein structures [26,40].
In recent decades, many computational studies have been per-
formed to characterize the p-stacking interactions in the active
sites of proteins, which are highly informative about the nature and
importance of these interactions [41e45]. Intermolecular p-stack-
ing interactions are also occurred in the crystal structures of fla-
vonoids due to the planarity, polarity, and aromaticity [46,47].
The inhibition mechanism of cytochrome P450 2C9 (CYP2C9)
has previously been investigated via a series of flavonoids [10]. The
results demonstrated that all the tested flavonoids are reversible
inhibitors of CYP2C9 and among them, 6-hydroxyflavone acts as

http://dx.doi.org/10.1016/j.molstruc.2016.08.040
0022-2860/© 2016 Elsevier B.V. All rights reserved.
14 F.B. Akher et al. / Journal of Molecular Structure 1128 (2017) 13e20
noncompetitive inhibitor and other flavonoids are competitive in-
hibitors. In addition, the work used computer aided docking and
molecular dynamic simulation to characterize the binding sites of
flavonoids in CYP2C9. Results indicated that the competitive in-
hibitors bind to the substrate binding site whereas the noncom-
petitive inhibitor binds to the allosteric site of the enzyme via a p-
stacking interaction with Phe100 residue and the hydrogen bonds
with Leu102 and Arg105 residues. The inhibitory mechanism of the
b-hydroxyl-acyl carrier protein dehydratase of Helicobacter pylori
(HpFabZ) by three flavonoids (S)-sakuranetin, quercetin and api-
genin has been studied by Zhang and coworkers [11]. These flavo-
noids were identified to be competitive inhibitors and bind to
HpFabZ via two models. In one model, flavonoids act as enzyme
inhibitors via noncovalent interactions and are stacked with two
residues Tyr100 and Pro112. Elsewhere, Pawlotsky and coworkers
[12] investigated the inhibition process of hepatitis C virus RNA-
dependent RNA polymerase (HCV RdRp) by six flavonoids. Quer-
cetagetin (QUE), a type of flavonol indicated in Scheme 1, was found
to be a more potent inhibitor in comparison with other flavonoids.
The X-ray structure of the HCV RdRp-QUE complex shows that QUE
binds to allosteric site of enzyme and alter its 3D structure. This
binding is done through noncovalent interactions (a hydrogen bond
with G238 and a p-stacking interaction with Phe162 residue),
which are poorly described by density functionals.
Moreover, p-stacking interactions may also affect the antioxi-
dant action of flavonoids. In fact, the activity of phenolic antioxi-
dants is not solely dependent on their structures. It may also be
affected by the noncovalent interactions in the surrounding envi-
ronment [2], particularly p-stacking interactions. Thus, it is impor-
tant to investigate the p-stacking interaction between flavonoids
and aromatic AAs and its effect on their antioxidant activity.
In the present work, the p-stacking interactions of QUE and
some amino acids containing five and six-membered aromatic rings
have been investigated at the M06-2X/6-311þþG(d,p) level of
theory. The complexes have been investigated with respect to the
energy data and the results of the population analyses. Herein, the
highest occupied molecular orbital (HOMO) and the lowest unoc-
cupied molecular orbital (LUMO), bond dissociation energies (BDE),
and Muliken spin density distribution (MSD) values have been
considered to investigate the antioxidant activity of stacked QUE.
This study can provide an insight about the magnitude of p-stacking
interactions between the aromatic AAs and QUE and their effect on
antioxidant activity of QUE, which is useful in biological processes.
2. Computational details
All calculations were carried out using the Gaussian09 program
Scheme 1. The structure of quercetagetin (3,5,6,7,30 ,40 -hexa hydroxy flavonol).
package [48]. All units were fully optimized by the hybrid meta
exchange-correction functional M06-2X [49] method in conjunc-
tion with the 6-311þþG(d,p) basis set. The nucleotide units were
modeled by replacing a hydrogen atom with the protein backbone
of AAs (indole for TRP, phenol for TYR, benzene for PHE and
imidazole for HIS). The initial structures of AAjjQUE complexes
(where jj donates p-stacking interaction) were generated by
aligning the centers of rings of units. Four parameters including
vertical separation (R1), rotational angle (a), and horizontal
displacement (R2 and R3), were considered to determine the
optimal complexes (see Scheme 2). The potential energy surface
scans were carried out through the single point calculations at the
M06-2X/6-311þþG(d,p) level to obtain the optimized geometries
of the AAjjQUE complexes. The preferred R1 value was obtained by
0.1 increments and held constant for the remaining calculations.
Then, AA was rotated by 360 (12 steps of size 30 ) for a increments
in right-handed sense about the axis that passes through the cen-
ters of rings. Using the optimal values for a and R1, the optimal
values of R2, and R3 were determined upon the shift of AA across
the face of QUE in 0.1 increments. All the above mentioned steps
were performed for three rings of QUE, which specified by A, B and
C letters in Scheme 1. After finding the best orientations of AAs
relative to the rings A, B and C of QUE, the most stable complexes
were obtained by optimization at the M06-2X/6-311þþG(d,p) level
of theory. No imaginary frequency was found for any of the opti-
mized structures. In addition, single point interaction energies
were calculated by the B3LYP-D3 [50,51] dispersion corrected
functional as suggested by Grimme for noncovalent contacts
[52,53]. The basis set superposition error (BSSE) correction was
performed by the counterpoise (CP) method. Also, to investigate
the effect of p-stacking interaction on the antioxidant activity of
QUE, radical structures of QUE and stacked QUE were optimized at
the above mentioned level. The topological properties of electron
charge density were calculated by the atoms in molecules (AIM)
method [54] using the AIM2000 program package [55] on the wave
functions obtained at the HF/6-311þþG(d,p) level of theory. The
natural bond orbital (NBO) analysis [56] has been performed on
those wave functions by the NBO3.1 software [57]. Moreover, MSDs
for radical species have also been calculated and interpreted.
3. Results and discussion
The interaction energies (DE) obtained for each step along the
scans of variables, introduced in the previous section, are available
in Supplementary material (see Table 1S). The largest DE values
calculated between AAs and the rings A, B and C of QUE are re-
ported in Table 1. The trend in the jDEj values is B < A < C in stacking
Scheme 2. Definition of variables in the AAjjQUE-C complexes.
 F.B. Akher et al. / Journal of Molecular Structure 1128 (2017) 13e20 15

with each AA. As can be seen in Table 1, the orders of the DE values
are identical at the M06-2X/6-311þþG(d,p) and the B3LYP-D3/6-
311þþG(d,p) level.
The presence of carbonyl group in the ring C of QUE can be a
reason for the more stability of the AAjjQUE-C complex. The elec-
tron withdrawing character of C]O in the ring C can reduce the
negative charge of p-electron cloud that decreases the repulsion
between the rings and makes more favorable the electrostatic in-
teractions. Also, two intramolecular hydrogen bonds between
C4¼O and the 3-OH and 5-OH groups can reduce repulsion be-
tween the rings. The 5-OH group located in meta position relative
to the 7-OH group in the ring A acts as an electron withdrawing
group via the inductive effect. This effect makes AAjjQUE-A more
stable than AAjjQUE-B through reduction of the negative charge of
Fig. 1. Correlation between the DE and CT values.
p-electron cloud.
Higher jDEj values are obtained from horizontal displacement in
the R2 direction, because of increase in the p-p overlap and favorite M06-2X/6-311þþG(d,p) level are summarized in Table 1. The
contacts between rings, which shift AAs toward the ring C. calculated binding energy is in the range of 7.6e11.5 kcal mol1 and
In addition, the sum of atomic ChelpG charges on the atoms of trend in the stability of complexes is similar to that found in the
the rings A (C atoms, qA), B (C atoms, qB) and C (C and O atoms, qC) potential energy surface scan. The optimized geometries of the
were calculated for QUE before stacking. It is interesting to note AAjjQUE-C complexes and the most important geometrical pa-
that qC (0.445) is more positive in comparison with qB (0.071) and rameters are gathered in Fig 2. Relative orientations of units remain
qA (0.244) in QUE. So, the ring C can be more susceptible to p- approximately constant after geometry optimization of complexes,
stacking interactions due to the lower negative charge of p-electron so the potential energy surface scans through the single point
cloud that results in more favorable electrostatic interactions. On calculations can be suitable in order to predict the optimal com-
the other hand, qB is negative while qA is positive. This can be a plexes. Charge delocalization between the rings A and B is done via
reason of decrease in the electrostatic repulsion between stacked the C2eC3 bond (see Scheme 1); this role can justify the effect of p-
rings and more stability of the AAjjQUE-A complexes relative to stacking interaction on the C2eC3 bond length. As can be seen in
AAjjQUE-B. Fig. 2, the trend in the C2eC3 bond length of the AAjjQUE-C com-
Charge transfer (CT) has frequently been used to predict the plexes is TRP > TYR > PHE > HIS. The complexes become less stable
intermolecular overlap and the stability of p-stacking complexes by decrease in the C2eC3 bond length, which is a result of
[58]. The amount of CT between AA and QUE was determined as the decreasing the charge delocalization.
sum of atomic charges calculated on the QUE fragment (see The trend in the hydroxyl bond lengths is 5-OH > 3-OH > 7-OH
Table 1). A relatively good correlation is found between the DE > 6-OH > 30 -OH > 40 -OH in the AAjjQUE-C complexes. Higher 5-OH
values and CT for the most stable AAjjQUE-X complexes (R ¼ 0.90, and 3-OH bond lengths can be related to the formation of two
see Fig. 1). Thus, it can be concluded that the electrostatic inter- strong hydrogen bonds between those groups and the C4¼O
action plays an important role in the stability of complexes. carbonyl group of ring C. The 5-OH$$$O4 distance is shorter than 3-
The trend in the jDEj values obtained for the stacking of AAs with OH$$$O4, so the 5-OH bond is longer than 3-OH. Therefore, there is
the ring C (the most stable complexes) is HIS < PHE < TYR < TPR. An a linear correlation between the OH bond length and the strength
identical trend can also be obtained for the size of AAs, in agree- of intermolecular H-bond. As seen, the OH bond lengths are shorter
ment with the relative surface area, polarizability and dipole mo- in ring B relative to those in rings C and A. Lower tendencies for
ments of the amino acids. intramolecular H-bond formation are accompanied with the
The most stable complexes (AAjjQUE-C) were optimized after shorter OH bond lengths in ring B.
finding the preferred orientation of each AA relative to QUE by the It should be noted that after optimization, correlation between
potential energy surface scans, the energy data obtained at the the DE values of the AAjjQUE-C complexes and CT increases from
0.91 to 0.93. The ChelpG charges implicate CT from ring B to rings A
and C. Also, a good linear correlation is observed between the
Table 1 stabilization energy of complexes and the sum of atomic charges on
BSSE corrected interaction energies (DE in kcal mol1) of the AAjjQUE-C complexes P
the rings A and C ( qAC ¼ qA þ qC, see Fig. 3).
calculated at the M06-2X/6-311þþG(d,p) level of theory, the value of CT (10 in e)
between AA and QUE, and the LUMO-HOMO energy gap (DELH in eV).
In order to investigate the reactivity of the AAjjQUE-C com-
plexes, the LUMO-HOMO energy gaps (DELH ¼ ELUMO-EHOMO) were
Complex AA R2 DE a
DE CT DELH calculated. As can be seen in Table 1, the trend of the DELH values
AAjjQUE-A TRP 1.4 8.8 10.3 11.9 e increases as TRP < TYR < PHE < HIS, which is inversely related to
TYR 1.4 7.2 8.6 4.4 the stability of the complexes. DELH is an important parameter to
PHE 1.5 6.7 7.9 3.7
describe the reactivity of complexes toward the free radical. The
HIS 1.4 6.1 6.8 0.7
AAjjQUE-B TRP 1.1 7.5 8.5 16.7 e TRPjjQUE-C complex has the lowest DELH value (higher softness),
TYR 1.2 5.1 6.1 11.4 which means the complex can behave as a better antioxidant in
PHE 1.3 4.4 5.1 9.6 comparison with other complexes.
HIS 1.5 5.6 6.0 13.5
AAjjQUE-C TRP 0.8 9.5, 11.50 10.8,11.7 18.2 21.08
TYR 0.8 8.4, 9.20 9.1,9.4 0.7 21.47
PHE 0.8 7.1, 7.70 7.8,8.1 5.0 21.60 4. AIM and NBO analyses
HIS 0.9 6.5, 7.60 7.0,7.3 5.3 21.72
a
BSSE corrected interaction energies of the AAjjQUE-C complexes calculated at
AIM analysis has been used to distinguish the strength of the
the B3LYP-D3/6-311þþG(d,p) level. The bold values correspond to the complexes noncovalent interactions involved in the AAjjQUE-C complexes.
optimized at the M06-2X/6-311þþG(d,p) level. Topological properties of the electronic charge density of the
16 F.B. Akher et al. / Journal of Molecular Structure 1128 (2017) 13e20

P
Fig. 2. The AAjjQUE-C complexes optimized at the M06-2X/6-311þþG(d,p) level. The C2eC3 and OH bond lengths are in Å, and CHELPG charges are in e. qAA-B is the sum of
P P P
charges on the ring B and AA ( qAA-B ¼ qAA þ qB), and qA-C is sum of the charge on the rings A and C ( qA-C ¼ qA þ qC).

Fig. 3. Correlation between the DE values and the sum of the charges on the rings A
and C.
complexes have been calculated by the AIM method on the wave
functions generated at the HF/6-311þþG(d,p) level of theory. A
typical molecular graph of AAjjQUE-C is presented in Scheme 3.
Scheme 3. A typical molecular graph of the AAjjQUE-C complex. The small red, green,
and yellow spheres correspond to BCPs, CCPs and RCPs, respectively.
Bond critical points (BCPs), ring critical points (RCPs), and cage
critical points (CCPs) were illustrated in this graph. The sum of
P P
electron densities calculated at BCPs and CCPs ( rBCPs and rCCPs)
P P
are shown in Table 2. The highest/lowest value of rBCP and rCCPs

Table 2
P P P
The rBCP and rCCP values calculated at the BCPs observed between the rings, the rRCP values calculated at the RCPs of rings A, B and C and their summation ( rRCP), the rBCP
P
values corresponding to the intramolecular hydrogen bonds in QUE and their summation ( rBCP) obtained from AIM analysis on the wave function produced at the HF/6-
311þþG (d,p) level of theory in e/au3.
P P
AA rBCP rCCP rRCP rBCP
P P
A C B rRCP HB1 HB2 HB3 rBCP
TRP 3.863 1.489 2.107 2.140 2.192 6.440 1.831 2.399 3.728 7.958
TYR 3.775 0.957 2.101 2.137 2.190 6.428 1.835 2.444 3.554 7.833
PHE 3.432 0.888 2.096 2.137 2.189 6.421 1.701 2.395 3.576 7.672
HIS 2.468 0.506 2.092 2.135 2.188 6.416 1.714 2.469 3.453 7.636
e e 2.079 2.125 2.177 6.381 1.758 2.410 3.436 7.604

The bold values correspond to QUE before stacking.

 F.B. Akher et al. / Journal of Molecular Structure 1128 (2017) 13e20 17

Fig. 7. Correlation between DE and the sum of the donor-acceptor interaction energies
▪
Fig. 4. Correlation between the DE and rRCP values of the rings A ( ), B (
:
) and C ().
P
of HB1, HB2 and HB3 ( E2HB).

Table 4
Bond dissociation enthalpy (BDE in kJ mol1) calculated at the M06-2X/6-
311þþG(d,p) level of theory for the AAjjQUE-C complexes.

BDE

AA 30 -OH 40 -OH 3-OH 5-OH 6-OH 7-OH

TRP 372.48 325.53 353.13 369.50 328.41 411.13

TYR 371.71 326.64 355.80 377.20 334.42 381.98
PHE 372.93 326.69 354.83 378.28 334.69 472.34
HIS 374.37 327.21 349.18 372.94 333.11 471.99

to describe interactions of the aromatic rings. The electron charge

density calculated at the RCP (rRCP) are also summarized in Table 2.
Fig. 5. Correlation between DE and the sum of rBCPs calculated at the intramolecular H- As can be seen, the p stacking interaction increases the rRCP values
bonds.
of the rings A, B and C of QUE. The DE values correlate with the rRCP
values of QUE, such that the stability of complexes increases by
Table 3 increasing the rRCP values of the rings A, B and C (see Fig. 4).
The donor-acceptor interaction energies (in kcal mol1) obtained from the NBO The AIM analysis reveals the presence of three intramolecular
analysis on the wave functions calculated at the HF/6-311þþG(d,p) level for the hydrogen bonds 5-OH$$$O4 (HB1), 3-OH$$$O4 (HB2) and 3-O$$$60 -
AAjjQUE-C complexes. H (HB3) in the AAjjQUE-C complexes. The rBCP values of the intra-
aP 2 bP 2 molecular hydrogen bonds are presented in Table 2. The rBCP values
AA E2AA/QUE E2QUE/AA E E2HB1 E2HB2 E2HB3 E HB

TRP 3.71 4.91 8.62 1.60 3.41 16.47 21.48

increase as HB3 < HB2 < HB1 in each complex. The p-stacking
TYR 3.10 3.36 6.46 1.73 3.58 14.83 20.14 interaction can affect the strength of intramolecular hydrogen
PHE 2.78 3.19 5.97 1.16 3.39 15.05 19.60 bond. A reasonable correlation is observed between the DE values
HIS 2.22 3.67 5.89 1.17 3.79 13.95 18.91 and the sum of rBCPs calculated at the intramolecular hydrogen
a P 2 P P
E ¼ E2AA/QUE þ E2QUE/AA. bonds (see Fig. 5).
b P 2
E ¼ E2HB1 þ E2HB2 þ E2HB3. The donor-acceptor interaction energy (E2) can also be used as a
measure of the strength of the noncovalent interactions involved in
the AAjjQUE-C complexes. The data obtained from the NBO analysis
corresponds to the TRPjjQUE-C/HISjjQUE-C complex. The stabilities
P P are shown in Table 3. The sum of the E2 values for interactions
of the complexes increase by increasing the rBCP and rCCP P P P
P P between AA and QUE ( E2 ¼ E2AA/QUE þ E2QUE/AA) can be
values. It demonstrates that the rBCP and rCCP values are useful
used as a descriptor for prediction of the DE values of the

Fig. 6. Correlation between DE and the sum of the donor-acceptor interaction energies
P
observed between AA and QUE ( E2). Fig. 8. Correlation between BDE and HOMO-LUMO energy gap (DELH).
18 F.B. Akher et al. / Journal of Molecular Structure 1128 (2017) 13e20

Fig. 9. MSD on QUE in the AAjjQUE-C complexes.

P 2
complexes. The highest/lowest E value corresponds to the strength of the intramolecular hydrogen bonds. Table 3 shows that
TRPjjQUE-C/HISjjQUE-C complex. As can be seen in Fig. 6, a the E2 values increase as HB3 < HB2 < HB1 in each complex, which
P
reasonable correlation is observed between the DE and E2 values. is in agreement with the data obtained from the AIM analysis. Good
In addition, the E values of the nO4/s*5OH, nO4/s*3OH and
2
linear correlations are observed between the E2 and rBCP values of
nO3/s*60 CH interactions can be considered as measures of the the intramolecular hydrogen bonds (R ¼ 0.98 for HB1 and HB2, and
 F.B. Akher et al. / Journal of Molecular Structure 1128 (2017) 13e20
R ¼ 1.00 for HB3). Also, the sum of the E2 values of HB1, HB2 and
P
HB3 ( E2HB ¼ E2HB1 þ E2HB2 þ E2HB3) can be used as a descriptor to
predict the stability of the complexes (see Fig. 7).
5. Bond dissociation energy (BDE)
The OH BDEs of QUE in the AAjjQUE-C complexes are important
parameters to evaluate the antioxidant activity [59]. The lower BDE
values indicate higher hydrogen donation ability from the OH
groups [5]. The OH BDEs of QUE have been calculated by the
following equation
BDE ¼ H(AAjjQUE-O) þ H(H)  H(AAjjQUE-OH)
where AAjjQUE-OH indicates the parent complex and AAjjQUE-O
is the corresponding radical. The enthalpy value of H was calcu-
lated to be 0.495834 hartree at the M06-2X/6-311þþG(d,p) level.
From Table 4, it is obvious that the lowest values of BDE in all
complexes are attributed to the 40 -OH and 6-OH groups on the rings
B and A, respectively in the complexes. H atom abstraction of the 40 -
OH and 6-OH groups leads to the formation of a relatively strong
intramolecular hydrogen bond (OH/O) with the OH group located
at adjacent carbon (30 -OH$$$O40 and 7-OH$$$O6) that may be the
reason of more stability of the AAjjQUE-O40  and AAjjQUE-O6
radicals. On the other hand, the results indicate that the H atom
abstraction from the 40 -OH group (ring B) is easier than 6-OH (ring
A). Charge delocalization is happened for the 40 -OH radical via the
C2eC3 bond, while such a delocalization is not observed for the 6-
OH radical [3]. The higher BDE values in the AAjjQUE-O3 and
AAjjQUE-O5 radicals can be attributed to the intramolecular
hydrogen bonds of 3-OH and 5-OH with the C4¼O group. The 5-
OH$$$O4 H-bond is stronger than 3-OH$$$O4, so the BDE value of
5-OH is higher than 3-OH.
The highest value of BDE is observed for the 7-OH group of the
complexes. The existence of the 5-OH group in QUE can increase
the 7-OH BDE in comparison with other OH groups. The 5-OH
group located in the meta position of the 7-OH group behaves as
an electron withdrawing group and enhances the BDE value of 7-
OH.
The order of BDE for 40 -OH is found to be TRP < TYR < PHE < HIS
in the complexes; this is in agreement with the DELH values of the
complexes. There is a good relationship between reactivity of
complexes and antioxidant activity of stacked QUE (see Fig. 8). The
p-stacking interaction slightly decreases the 40 -OH BDE and in-
creases the antioxidant activity of QUE.
MSD can be used as a realistic parameter to describe the reac-
tivity [60]. The antioxidant ability of QUE in the AAjjQUE-C com-
plexes can also be visualized via the MSD analysis of corresponding
radicals. Therefore, in order to discuss the reactivity of different OH
groups of QUE and consequently the variations in the BDE values,
MSD analysis has been performed on various QUE radical forms of
the complexes. A higher MSD in a radical leads to a lower BDE and
makes easier radical formation [61]. As can be seen in Fig. 9, the
highest MSD corresponds to the AAjjQUE-O40  radicals. This can be
attributed to the C2eC3 bond which allows the MSD distribution on
two rings B and C. This result can also be explained by high spin
density on the C0 1 atom at para position of the 40 -OH group in the
AAjjQUE-O40  radicals, and spin delocalization via the C2eC3 bond
by resonance. There is not such a delocalization for the AAjjQUE-
O6 radicals which is in agreement with the BDE data. In addition,
higher MSDs for the AAjjQUE-O3 radicals in comparison with the
AAjjQUE-O5 radicals confirm the lower BDE value for 3-OH. The
atomic MSD is delocalized on two rings B and C in the AAjjQUE-O3
radicals, while it just is delocalized on the ring A in AAjjQUE-O5.
On the other hand, the lowest MSD corresponds to the AAjjQUE-O7
19
radicals which is in agreement with the highest BDE value corre-
sponding to the related complexes.
6. Conclusions
In the present study, the quantum mechanical calculations were
used to characterize the stacking interactions utilized by QUE. To
the best of our knowledge, this is the first study that considers the
staking interactions between QUE as a flavonol and four aromatic
AAs, and therefore the effect of that interaction on the antioxidant
activity of QUE. This information can be useful since the magni-
tudes of descried p-stacking interactions are difficult to obtain
directly from experiments where it is hard to separate other effects.
A broader understanding of the effects of charge on both the
preferred geometries and the magnitude of the binding energies
has been revealed in the AAjjQUE-X complexes. The results indicate
that the ring C in QUE is more suitable than the rings A and B for the
p-stacking interaction. The sum of atomic ChelpG charges on the
atoms of the ring C is more positive than those of A and B, which
results in more favorable electrostatic interactions and therefore
stronger p-stacking interactions. A relatively good correlation is
found between the DE values and CT for the most stable AAjjQUE-X
complexes. On the other hand, the interaction energies of the most
stable complexes (AAjjQUE-C) with respect to AAs decrease as
TRP > TYR > PHE > HIS, which this trend is dictated by the relative
surface area, polarizability and dipole moments of AAs. The stability
of complexes is accompanied with decrease in the C2eC3 bond
length, which is a result of decreasing the charge delocalization.
Reactivity of the AAjjQUE-C complexes estimated using the LUMO-
HOMO energy gap decreases as TRP > TYR > PHE > HIS.
According to the AIM analysis, the complexes become more
P P
stable by increasing the rBCP and rCCP values obtained between
P P
rings. So, it demonstrates that the rBCP and rCCP values are
useful to describe interactions of the aromatic rings. On the other
hand, The NBO analysis shows that the sum of donor-acceptor
interaction energies between AA and QUE
P P P
( E2 ¼ E2AA/QUE þ E2QUE/AA) increases by increasing the DE
values of the complexes.
The lowest values of BDE corresponds to the 40 -OH and 6-OH
groups on the rings B and A, respectively, in the complexes. The p-
stacking interaction slightly decreases the 40 -OH BDE such that the
trend becomes HIS > PHE > TYR > TRP and confirms the positive
effect of p-stacking in increasing the antioxidant reactivity of QUE.
On the other hand, the most MSD in the radical species corresponds
to AAjjQUE-O40 , which is in agreement with the BDE data.
Acknowledgment
We thank the University of Sistan and Baluchestan for financial
supports and Computational Quantum Chemistry Laboratory for
computational facilities.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2016.08.040.
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