Vol.3, No.7, 573-579 (2011) Natural Science
http://dx.doi.org/10.4236/ns.2011.37080
Copyright © 2011 SciRes. OPEN ACCESS
A quantum-chemical model of the inhibition mechanism
of viral DNA HIV-1 replication by Iodine complex
compounds
Gulnara Abd-Rashidovna Yuldasheva1, Georgii Mihailovich Zhidomirov2, Aleksandr Ivanovich Ilin1
1Anti-Infective Drug Research Center, Almaty, Kazakhstan; *Corresponding Author: yuldasheva57@rambler.ru, ilin_ai@mail.ru
2Boreskov Institute of Catalysis SB RAS, Novosibirsk, Russia; *Corresponding Author: zhidomirov@mail.ru
Received 21 March 2011; revised 15 April 2011; accepted 21 April 2011.
ABSTRACT
The interaction of molecular iodine with virus
DNA nucleotide is studied by ab initio RHF/3-
21G** method. Formation of the nucleoprotein
complex of the HIV DNA, molecular iodine and
the HIV-1 integrase co-factor is considered to
cause the inhibition action of the integrase en-
zyme. Experimental data on the anti-HIV effect of
the molecular iodine complex compounds and
the results of calculations suggest that mole-
cular iodine contained in iodine polymer com-
plexes may be considered as a compound inhi-
biting the catalytic center of the integrase en-
zyme. Unlike the known integrase inhibitors,
molecular iodine also changes the virus DNA
structure and produces the N-I bond in the
purine bases of adenosine and guanosine nu-
cleotides.
Keyw ords: HIV; Integrase HIV; Quantum-Chemical
Method Ab Initio
1. INTRODUCTION
The human immunodeficiency virus (HIV) belongs to
the series of retroviruses whose gene within the virion is
represented by a RND molecule. After the virus pene-
trates a human cell, a DNA copy of the virus genome is
synthesized and such virus DNA is integrated into the
genome of the human cell. Both processes are produced
by the virus enzymes – transcriptase and integrase [1],
respectively.
A large number of agents inhibiting the activity of the
HIV reverse transcriptase have been developed [2] and
used for medicine production. However, the HIV reverse
transcriptase is referred to the class of polymerases and
most of its blockers that, to some extent, suppress the
actions of this class of cellular enzymes producing sig-
nificant toxic effects [3,4].
HIV integrase inhibitors have a high therapeutic effect
[5] for two reasons. First, integrase is one of the key
participants in the virus replication cycle [1]. Second,
integrase has no cellular equivalent and, hence, the sup-
pression of its activity should not disturb normal cellular
metabolism processes [6].
HIV-1 integrase contains 288 amino acid residues and
three domains can be distinguished in its structure: a
short N-end domain containing 1-50 amino acid residues,
a catalytic domain producing 51-212 amino acid resi-
dues and a C-end domain containing 220-270 amino acid
residues.
It is typical for such family of enzymes to produce
very stable complexes with a virus DNA. To be inte-
grated, it is necessary for integrase to bind both - virus
and cell - DNA molecules at the same time. The integra-
tion proceeds in two stages and begins in the cytoplasm
of HIV infected cells where, upon completion of the
reverse transcription of the virus DNA genome, integrase
binds the virus DNA copy producing the so-called pre-
integration complex (PIC) which can be isolated from
the HIV-infected cells [7].
A model of the integrase structure in the complex with
a virus and a cell DNA was proposed in [8]. According
to the model, only the catalytic domain takes part in the
binding of the virus DNA, while all the three domains
take part in the binding of the cell DNA.
The structure of the catalytic domain of the HIV-1 in-
tegrase is determined by the X-ray structural analysis.
According to the data obtained, the catalytic domain of
the enzyme in the crystal forms a spherical dimer with
each monomer forming a semi-sphere. The three amino
acid residues - Asp64, Asp116 and Glu152 closely lo-
cated in the tertiary structure of the catalytic domain –
form its active catalytic center with the active centers of
each integrase monomer located on the opposite sides of
the dimer sphere 35 Å apart.
The X-ray structural analysis data clearly show one
Mg2+ ion coordinated by Asp64 и Asp116 and two water
G. A.-R. Yuldasheva et al. / Natural Science 3 (2011) 573-579
Copyright © 2011 SciRes. OPEN ACCESS
574
molecules [9,10]. Based on data regarding the action
mechanism of nucleotidyltransferases [11], referred to
the same family as the HIV-1 integrase, it was suggested
in [12] that two ions may take part in the act of catalysis,
but, due to a higher conformational mobility of the cata-
lytic enzyme, they are not coordinately bound prior to
being bound with the virus DNA. With the use of the
molecular dynamics method it was shown that the inter-
action with the virus DNA involves the integration of
two Mg2+ ions into a stable bi-nuclear structure where
the amino acid residue Glu152 simultaneously coordi-
nates the two Mg2+ ions, while Asp64 and Asp116 inter-
act only with one of the Mg2+ ions.
In the paper [13] the authors offer a comparison of the
inhibiting activity of a series of antiretroviral agents to-
wards HIV-1 integrase and the in vitro-isolated PIC. The
results of the study show that inhibitors active towards
the integrase enzyme may not be active towards the PIC.
The capability to inactivate a PIC was exhibited only by
three antiretroviral agents: quinalizarin, purpurin, and
alizarin.
There is a whole range of iodine polymer complexes
with an anti-HIV effect [14-17]. For example, complexes
of iodine with polyurethane polymers rapidly, within
15-20 minutes inactivate HIV-1. However, the authors of
[14-18] do not propose a mechanism of inactivation of
HIV. A model of the HIV-1 inhibition by molecular io-
dine within the framework of ab initio RHF/3-21G**
method is proposed in this work. It is suggested that
molecular iodine may prevent PIC formation.
The results of the study are summarized in three sec-
tions. The first section deals with the selected computa-
tional method tested on model structures. The structure
and nature of the molecular iodine interaction with virus
DNA nucleotides is studied by the ab initio RHF/3-21
G** method in the second section. A model of the me-
chanism of inhibition of the HIV-1 integrase enzyme in
the nucleoprotein complex formed by the virus DNA by
molecular iodine and the catalytic enzyme co-factor is
proposed in the third section. Calculations were per-
formed using the Gaussian 03 program.
2. METHOD
The purine and pyrimidine bases of nucleotides in-
clude nitrogen and oxygen hetero atoms. The formation
of stable complexes of molecular iodine with compounds
including such hetero atoms is confirmed by thermody-
namic data [19,20] and data obtained by physical re-
search methods (UV-spectroscopy, X-ray structural an-
alysis) [19,21].
The RHF/3-21G**, DFT PBE/3-21G** [22] methods
were used for calculating the structure and stability of
iodine complexes with pyridine and quinoline isomers
(Figure 1, Table 1). Charges are calculated according to
the Mulliken’s scheme.
N
1
I
7
I
8
2
3
4
5
6
N1
I7
I8
2
3
4
5
6
2
3
4
5
6
N
1
I
7
I
8
(1) (2) (3)
Figure 1. Molecular iodine complexes with pyridine and quinoline isomers.
Table 1. Bond length (Å), charge transfer (q), theoretical (Htheor., kJ/mole) and experiment (Hexp., kJ/mole) heat of formation for
iodine complexes with pyridine and quinoline isomers.
N
1-C2 C2-C3 C3-C4 C4-C5 C5-C6 C6-N1 N-I I-I HtheorHexpq
I 1.33 1,38 1.39 1.39 1.38 1.33 2.68 2.7436.12 31.30 - 35.990.108
II 1.30 1.41 1.42 1.36 1.41 1.36 2.75 2.7431.98 30.25 0.100
RHF/3-21G**
III 1.37 1.35 1.42 1.40 1.42 1.30 2.68 2.7436.45 34.90 0.110
I 1.36 1.40 1.41 1.41 1.40 1.36 2.57 2.8078.80 31.30 - 35.990.221
II 1.34 1.42 1.39 1.43 1.44 1.38 2.50 2.8179.53 30.25 0.230
PBE/3-21G**
III 1.38 1.38 1.43 1.44 1.42 1.34 2.47 2.8180.28 34.90 0.234
G. A.-R. Yuldasheva et al. / Natural Science 3 (2011) 573-579
Copyright © 2011 SciRes. OPEN ACCESS
575
The X-ray structural analysis data for the complex of
I2 with methylpyridine show that RN-I = 2.31 Å, while
RI-I ranges from 2.67 Å in a free I2 molecule to 2.83 Å in
the complex [21]. The DFT PBE/3-21G** RHF/3-21G**
methods give a longer N-I bond, while the length of the
I-I bond is close to the experiment.
The capability of the method to correctly reproduce
the geometry of charged polycations and polyanions of
iodine was tested on the structures (Figure 2). The RHF/
3-21G** method gives interatomic distances close to the
experiment [23] and correctly reproduces the geometry
of the ions (I5 (q = 1), I5 (q = 1), I3 (q = 1)).
The N-I bond is of a donor-acceptor nature, the for-
mation of the I-III complexes is accompanied by a
charge transfer to the I2 molecule (Table 1). UV spectral
data for iodine complexes with heterocyclic aromatic
bases are given in [19]. The formation of donor-acceptor
complexes results in a significance change in the elec-
tronic spectrum of the system: it is indicated by appear-
ance of strong 230 nm - 240 nm bands connected with
the charge transfer from the donor to the acceptor.
The heat of complex formation calculated by the DFT
PBE/3-21G** method (Htheor) is much overestimated,
while Htheor in RHF/3-21G** is close to the experiment
and correctly represents changes in the complex stability
depending on the position of the nitrogen atom in the
quinoline heterocycle (Table 1).
The presented data show that RHF/3-21G** may be
used for calculations of the structure and stability of io-
dine complexes with purine and pyrimidine bases of
nucleotides.
2.1. The Structure of Molecular iodine
Complexes with Nucleotides
The intercalation of the active substance of the drug
into the DNA structure is considered as a possible reason
by an anti-HIV effect [24]. The interaction of the active
substance of the drug with DNA results in the formation
of a new structure whose geometry and stability is de-
termined by the nature of interaction (stacking [25], a
donor-acceptor interaction) between the drug and nu-
cleotide triplets.
The RHF/3-21G** level of theory was used for stud-
ying the interaction of molecular iodine with deox-
yadenosine monophosphate IV(a,b), deoxycytidine mo-
nophosphate V and deoxyguanosine monophosphate VI
(Figure 3). In the calculations, the phosphate fragment is
replaced by a hydrogen atom on the assumption that the
phosphate fragment of the nucleotides should not sig-
nificantly affect the donor properties of the bases.
The calculation results show that in the interaction of
I2 with nucleotides the formation of donor-acceptor
complexes is energetically preferable. Coordination is
I
1
I
2
I
4
I
3
I
5
2.7
3.4 3.4
2.7
q=-1
2,92*
3,17* 3,17*
2,92*
I1I2
I4
I3
I5
2.7
q=1
2.7
2.9 2.9
2,73*
3,02*
2,73*
3,02*
I
1
I
2
I
3
q=1
2.7 2.7
2,75* 2,75*
Figure 2. Data X-ray and result of calculation done by method RHF/3-21G** (*) for iodine polycations and polyanions (Å).
N
3
N
1
N
N
N
7
H
H
9
H
8
I
I
O
H
H
H
HHO
HH
4
5
62
N
3
N
1
N
N
N
7
H
H
9
H
8
I
I
O
H
4
5
62
H
H
HH
OH
H
O
H
H
H
HH
H
C
2
N
3
N
1
N
7
H
8
H
9
I
I
4
5
6
O
OH
O
H
H
H
HH
H
OH
C
2
N
1
C
6
N
3
N
N
I
I
4
5
H
N
H
H
O
IVa IVb V I
Figure 3. Molecular iodine complexes with free deoxynucleotides.
G. A.-R. Yuldasheva et al. / Natural Science 3 (2011) 573-579
Copyright © 2011 SciRes. OPEN ACCESS
576
made by one of the nitrogen atoms of the purine or pyri-
midine bases of nucleotides with a negative charge trans-
ferred to the I2 molecule. The length of the N-I bond,
like in the complexes of I2 with pyridine and quinoline
isomers, is in the range of 2.5 Å - 2.7 Å, and the I-I bond
becomes weaker (Table 2).
Table 2 shows that the molecular iodine complex with
cytosine is the most energetically preferable, but in the
guanosine-cytidine pair the nitrogen atom of the pyrimi-
dine base takes part in the formation of the Watson-Crick
hydrogen bonds. The I-I bond is noticeably longer than
the hydrogen bonds and therefore, the formation of the
cytosine-molecular iodine complex should be accompa-
nied by the destruction of hydrogen bonds in the Wat-
son-Crick pair (Figure 4).
The influence of hydrogen bonds on the preferences
of complex formation in the nucleotide pairs of Watson-
Crick bases is studied on model structures of compli-
mentary pairs of purine and pyrimidine bases: adeno-
sine-thymidine, guanosine-cytosine, the sugar-phosphate
fragment of the nucleotides being replaced by the СН3-
group (Figure 4).
The calculations have shown that in the guanosinecyto-
sine pair iodine forms a stable complex with guanosine
via a connection with the nitrogen atom of the five-mem-
bered cycle. The formation of the I2 –cytosine complex is
accompanied by a break of the Watson-Crick hydrogen
bonds and, therefore, is not energetically preferable. In the
complimentary adenosine-thymidine pair, the nitrogen
atom of adenine which does not take part in the formation
of hydrogen bonds is also the most energetically prefer-
able atom for iodine coordination (Figure 4).
Table 2. Bond length (Å), charge transfer (q), stabilization energy (Еtheor., kJ/mole) for iodine complexes with deoxynucleotides.
N
1-C2 C2-N3 N3-C4 C4-C5 C5-C6 C6-N1 C4-N7 N-I I-I Еtheorq
IV(a) 1.33 1.33 1.34 1.40 1.38 1.33 1.34 2.64 2.75 49.32 0.120
IV(b) 1.31 1.35 1.34 1.40 1.38 1.34 1.34 2.68 2.75 46.72 0.117
RHF/3-21G**
V 1.40 1.37 1.31 1.43 1.34 1.35 1.34 2.68 2.75 53.25 0.121
VI 1.37 1.30 1.35 1.37 1.43 1.43 - 2.66 2.75 51.37 0.121
VII, E = –56.69 VIII, E = 31.80
IX, E = –45.12 X, E = 26.86
Figure 4. The influence of hydrogen bonds on the preferability of complex formation in complimentary Watson-Crick nu
cleotide base pairs. Е (kJ/mole) is the energy of complex formation by molecular iodine and the purine and pyrimidine
bases of nucleotide. Blue balls - carbon atoms, dark blue -nitrogen atoms, red- oxygen atoms, white-hydrogen atoms, vio-
let-iodine atoms.
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2.2. The Mechanism of Inhibition of the
HIV-1 Integrase Enzyme
The spatial and electronic structure of possible struc-
tures of the active center of the nucleoprotein complex
formed by the virus DNA, molecular iodine and the
fragment of the catalytic center of HIV-1 intergrase was
calculated (Figure 5).
The formation of I2-nucleotide complexes is accom-
panied by the delocalization of electron density along the
I-I bond and its weakening. In VII-X complexes the do-
nor properties of the I2 molecule are enhanced due to a
negative charge transferred to I2. The negatively charged
atom of I2, which is located far enough from the sugar-
phosphate backbone of the virus DNA and, thus, is read-
ily available, may prevent the active catalytic fragment
of HIV-1 integrase from interacting with the virus DNA.
Coordinating one of the Mg2+ ions, I2 may become the
center of another nucleoprotein complex in which mo-
lecular iodine interacts both with the virus DNS and the
active catalytic domain of HIV-1 integrase, exhibiting
acceptor properties with respect to nucleotides, and do-
nor properties with respect to the Mg2+ ions.
On the assumption that the coordination of nucleo-
tides of the virus DNA by molecular iodine prevents the
formation of a stable bi-nuclear structure with two Mg2+
ions in the catalytic domain, two possible variants of
Mg2+ coordination by carboxyl groups of the amino acid
residues Asp64, Asp116 and Glu152 were considered
(structures XI-XIV). In XI-XIV the hydrocarbon and
amide fragments of the amino acid residues were re-
placed by a methyl group. This simplification of the
structure of the amino acid residues Asp64, Asp116 and
Glu152 may be justified by the fact that the amide frag-
ment is separated from the carboxyl groups by several
methyl groups and, therefore, does not influence their
donor activity.
The calculations showed the possibility of formation
of a stable nucleoprotein complex in which molecular
iodine coordinates with both the purine bases of nucleo-
tides and the Mg2+ ion, significantly reducing the charge
on the magnesium ion (Table 3).
The stabilization energy of the nucleoprotein complex
Е is calculated as:
123I2
EE E+E+E  (1),
where E1—total energy of the structures XI-XIV;
I
2
I
1
XI, Q = 0 XII, Q = 0
XIII, Q = 1 XIV, Q = 1
Figure 5. Possible structures of the active center of the nucleoprotein complex formed by the virus DNA,
molecular iodine and the fragment of the catalytic center of HIV-1 intergrase. Blue balls-carbon atoms, dark
blue-nitrogen atoms, red-oxygen atoms, white- -hydrogen atoms, violet-iodine atoms, yellow–ion Mg2+.
G. A.-R. Yuldasheva et al. / Natural Science 3 (2011) 573-579
Copyright © 2011 SciRes. OPEN ACCESS
578
Table 3. Stabilization energy (Е, kJ/mole), spatial (interatomic bond, Å) and electron characteristics of possible models of the active
center of the nucleoprotein complex formed by the virus DNA, molecular iodine and the catalytic fragment of HIV-1 intergrase.
XI XII XIII XIV
Е 110.07 108.35 318.69 259.70
N-I 2.42 2.53 2.15 2.13
I-I 2.81 2.79 3.12 3.21
Mg-I 2.95 2.95 2.69 2.68
Q (I1) 0.204 0.187 0.396 0.432
Q (I2) –0.235 –0.186 –0.333 –0.365
Q (Mg) 0.767 0.789 0.775 0.758
*) QMgCOOCOO = 0.885; QMgCOOH2O = 1.099.
E2—total energy of Mg(COOCH3)2 for XI,XII and
Mg(COOCH3)H 2O for XIII, XIV;
E3—total energy of the Watson-Crick pair adeno-
sine-thymidine in XI, XIII and guanosine-cytosine in XII,
XIV;
EI2—total energy of I2 molecule.
In the structures XIII, XVI the I-I bond is broken and
RN-I indicates that there is a new N-I bond in the purine
bases of adenosine and guanosine (Table 3).
Among the recently developed drugs inhibiting the
activity of HIV-1 integrase there are those whose inhib-
iting activity is connected with the formation of coordi-
nation bonds with two Mg2+ ions [12,26] of the catalytic
fragment of HIV-1 integrase. The calculations revealed
that the molecular iodine contained in iodine polymer
complexes could be referred to this class of compounds,
but, unlike the known inhibitors of HIV-1 integrase, I2
also changes the structure of the virus DNA.
3. CONCLUSIONS
The computation results suggest that molecular iodine
in drugs containing molecular iodine complexes may be
referred to compounds inhibiting the catalytic center of
the HIV-1 integrase enzyme.
It is shown that molecular iodine prevents the forma-
tion of PIC and inhibits the HIV-1 intergrase enzyme
inside the nucleoprotein complex where I2 interacts both
with the virus DNA and the active center of the catalytic
domain of the HIV-1 intergrase exhibiting acceptor
properties with respect to the nucleotides of the virus
DNA and donor properties with respect to Mg2+ ions.
The breaking of the I-I bond and the formation of a
new N-I bond in the purine bases of adenosine and gua-
nosine may be observed in the structure of the nucleo-
protein complex.
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