Open Journal of Applied Sciences, 2012, 2, 98-103
doi:10.4236/ojapps.2012.22013 Published Online June 2012 (http://www.SciRP.org/journal/ojapps)
Drug-DNA Interaction: A Theoretical Study of the Stability
of CP-DNA Binding with Thionine
Ghazala Yunus*, Seema Srivastava, Vishwambhar Dayal Gupta
Department of Physics, Integral University, Lucknow, India
Received March 24, 2012; revised April 22, 2012; accepted May 9, 2012
ABSTRACT
The recent study on binding of small molecules to double stranded DNA suggested that the intercalation of a tricyclic
heteroaromatic molecule, thionine, with natural DNA provided thermal stabilization to the complex. In the present
study, we reported theoretical analysis of thionine binding with Clostridium perfringenes DNA duplex (CP-DNA) by
using an amended Zimm and Bragg theory, to explain the melting behaviour and heat capacity of CP-DNA with and
without thionine binding. The experimental models of Paul et al. (2010) have been used for the study. The sharpness of
transition has been examined in terms of half width and sensitivity parameter (∆H/σ). The results of theoretical ap-
proach suggested that the various parameters such as transition profile, sharpness of the transition, heat capacity curve
and half widths are in good agreement with the experimental measurements for binding of thionine. Therefore, the pro-
posed theoretical analysis may be useful in order to understand interaction of small molecules to DNA that may be ap-
plied in the process of drug development and for designing more potential DNA binding therapeutic molecules.
Keywords: Thionine; DNA Binding; Transition Profile; Heat Capacity; Drug Design
1. Introduction
The study of the interaction of small molecules with
DNA is a field of high tropical interest and the number
and verity of techniques devoted to evidence drug-DNA
interactions is continuously growing. The binding of het-
erocyclic aromatic molecules to nucleic acids has re-
ceived considerable attention over the past several years
due to their relevance in various biological applications
including cancer chemotherapy [1-8]. Accordingly, a
number of experimental studies are conducted to under-
stand the nature and thermodynamics of heterocyclic
aromatic molecules and nucleic acid interaction [7,9-16].
Thionine (3,7-Diamino-5-phenothiazinium) (Figure 1), a
tricyclic heteroaromatic molecule, has been studied for
its intercalative interaction with duplex DNA [13] and
photoinduced mutagenic actions on binding to DNA [11].
On the basis of satellite hole spectroscopy study Chang et
al. [17] recommended that thionine binds specifically
with guanine-cytosine (GC) contents of duplex DNA.
However, Tuite and Kelly [13] suggested that (GC)
specificity of thionine binding was not very marked. The
model proposed by Hecht et al. [18,19] suggested that
thionine exists in two different tautomeric forms and the
amino form is intercalated while the imino form is not.
Although these data provide somewhat cont radicting
data on the GC specificity of thionine binding to linear
double stranded DNA. A recent study [18] by pressure
tuning hole burning spectroscopy has conclusively
shown an external stacking mode of binding of thionine
to quadruplex structures. Thus, although some structural
data is available, the same is not conclusive and the
thermodynamics of thionine binding to DNA is not yet
elucidated. The calorimetric analysis of thionine binding
to a DNA duplex was reported by Paul et al. [7]. They
also investigated the structural and thermodynamic as-
pects of thionine binding to natural DNAs of varying
base composition. They showed strong binding of thion-
ine with CP-DNA which increases the thermal stability
of the duplex, and at saturation the duplex melts with a
Tm some 6.3˚C above that of the free duplex [7]. They
also concluded that binding of thionine to CP-DNA is an
exothermic process and there is involvement of multi-
plicity of non covalent interactions in the binding process.
In the present study, we have attempted to understand the
effect of thionine binding on a native DNA duplex using
the model of Paul et al. [7] who studied the thermal and
*Corresponding author. Figure 1. Chemical structure of thionine.

G. YUNUS ET AL. 99
thermodynamic behaviour of thionine binding to CP-DNA.
To elucidate lambda point anomalies in heat capacities
and order-disorder transition in thionine bounded and
unbounded DNA duplexes, we used amended Zimm and
Bragg theory which is considered initially for the helix
coil transitions in polypeptides [20-22]. The effect of
thionine binding is reflected in the change in nuclea-
tion parameter, which is an inverse measure of binding
strength.
2. Theory
The results of the structural studies proposed by Paul et
al. [7] for the complex of heterocyclic aromatic mole-
cules with DNA on the basis of spectroscopic and calo-
rimetric study, as mentioned above, suggested that thio-
nine binds strongly with the Clostridium perfringenes
DNA that resulted in thermal stabilization of the complex.
The binding of thionine to the AT rich Clostridium per-
fringenes DNA was intercalative and favored by higher
entropic contribution indicating the stronger perturbation
of the water structure associated with the AT sequences
[7]. However, the system remains a highly co-operative
one therefore the co-operative transition theory could be
applied to explain the melting profile and temperature
dependence of thermodynamical parameter, such as heat
capacity. Therefore, we can use amended Zimm and
Bragg theory [20] which is described in our previous
publication [23]. Briefly, the above mentioned theory
consists of writing an Ising matrix for a two-phase sys-
tem, the bounded state and unbounded state. As dis-
cussed earlier [21,22,24-26] and by Zimm and Bragg
[20], the Ising matrix M can be written as:
12 1212 12
12 1212 12
12 1212 12
0
0
0
rkh
rr rr k
kr kk h
hh rh h
fff
ff ff f
f
ff ff
f
ff ff
M (1)
where fr, fh and fk are corresponding base pair partition
functions’ contributions in the three states i.e. ordered,
disordered and boundary or nucleation. The eigen values
of M are given by:




12
2
1
12
2
2
3
4
4
0
rh rhrk
rh rhrk
ff ffff
ff ffff














(2)
Since we are dealing with a finite system hence the
effect of initial and final states becomes important. The
contribution of the first segment to the partition function
is given by:


12
,0,0
r
fU (3)
where the column vector V gives the state of the last
segment,
12
12
12
r
k
h
f
f
f
V (4)
The partition function for an N-segment chain is given
by;
1N
ZUMV (5)
The matrix T which diagnolizes M consists of the
column vectors given by:


MXX (6)
where,
1
2
3
X
X
X
X.
By substituting the values of M from Equation (6), we
get:








1112 12
12 1212 12
12 1212 12
1/21 2
11
1 1 1
()
()
rr
rk
rk rk
hr hr
hr
hh
ff
ff
ff ff
ff ff ff
ff







T (7)
Similarly, we get 1

T from the matrix equation

YMY (8)
where, 1, 2, 3 YYY





Y
Again by substituting the values of M from Equation
(1) in Equation (8), we get:







12 1212 12
11
1
111
12 1212 12
22
1
2
222
12 1212 12
33
3
333
rk krh
h
rk krh
h
rk krh
h
cf fcff f
Cf
cf fcff f
Cf
cf fcff f
Cf






T (9)
The normalization constants are:
12
12
12 21
,,
hh
ff
CC C

 

3
0



 (10)
If we let 1

TMT be the diagonalized form of M,
the partition function can be written as:
11
N ZUT TV (11)

G. YUNUS ET AL.
100
On substituting the values from Equations (1), (3), (4),
(7), (9) and (10) in Equation (11), the partition function
becomes:
here s is propagation parameter, which for simplicity is
assumed to be 1. In fact, in most of the systems, it is
found to be close to unity. If Ar and Ah are the absorbance
in disordered and ordered states, respectively, the total
absorption can be written as:
11 21
N
N
CC

 Z (12)
The fraction of the segments in the disordered form is
given by


1
rrr h
A
QAQ A (14)
The extension of this formalism to specific heat (Cv) is
straight forward. The specific heat is related to the molar
enthalpy and entropy changes in the transition from state
I to II. From the well known thermodynamic relations,
free energy and internal energy are ln
F
KT Z and




2,UT TFT
  respectively. Differentiating in-
ternal energy with respect to temperature we get the spe-
cific heat:


ln ln
rr
QZf  N
Solving the above equation, we get:







2
1211
121
1
22 2
r
s
AP s
sA
QPPN


  (13)
where 12
r
P
f

 

 
2
vkm
CUTNHRTSQS

r

   (15)

2
24
h
r
k
r
rh kr
f
sf
f
f
Aff ff







where
H

is the molar change in enthalpy about the
transition point, S is entropy which is equal to




exp11 m SHRTT


 

,
m
T is the transition temperature, and
 





 
   
2
3
2112 1
121
2
21
12
11211211
2
rPSASA P
QPA
SS S P
AP
PA
PSA PSA PS S
SS PN


 





 


 
 

 

  
 
 

 
   

 
 
21


with



23
21
2
N
N
r
SNS
A
S P
Zf


S





 

 
  

 







 




bound and free thionine [7]. When tricyclic heteroaro-
matic thionine binds with natural Clostridium perfringe-
nes DNA duplex, the structure of DNA duplex still re-
mains a very much co-operative and thus two-state the-
ory of order-disorder transition is applicable. The Zimm
and Bragg theory [7] is amended so as to consider or-
dered (bounded/unbounded) and disordered states as the
two states which co-exist at the transition point. The
transition is characterized mainly by the nucleation pa-
rameter and overall change of enthalpy/entropy, which
are also the main thermodynamic forces driving the tran-
sition. The change in enthalpy obtained from differential
scanning calorimetric measurements takes all this into
account. This is evident from the enthalpy change and
changes in other transition parameters, such as nucleation
parameter (σ) and melting point (Table 1). The melting
temperature of the duplex was increased after binding
with thionine at saturation. At saturation, the duplex
melts with a Tm some 6.5˚C above that of the free duplex.
The sharpness of the transition can be looked at in terms
of half width and a sensitivity parameter defined as
(∆H/σ). The variation of these parameters systematically
reflects that the transition is sharp in case of unbounded
state and goes blunt with thionine saturation. In case of

1PS SP   and kr
f
f

; σ is the nucleation
parameter and is a measure of the energy expanded/re-
leased in the formation (uncoiling) of first turn of the
ordered/disordered state. It is related to the uninterrupted
sequence lengths [20]. The volume heat capacity Cv has
been converted into constant pressure heat capacity Cp by
using the Nernst-Lindemann approximation [26]:

2
0
3

p
vp
CC RACTCT vm (16)
where A0 is a constant often of a universal value [3.9 ×
10–9 (Kmol)/J–1] and Tm is the melting temperature.
3. Results
3.1. Transition Profiles
The binding affinity of thionine with C-DNA has been
studied by spectroscopic, fluorescence and dialysis meth-
ods which showed strong intercalative binding and en-
abled the assumption of two state systems consisting of

G. YUNUS ET AL. 101
λ-transition, the same trend in the sharpness of transition
is seen between the thionine bounded as well as un-
bounded curves. As expected, the sharpness is better in
unbounded, as compared to bounded state. The various
parameters, which give transition profiles in best agree-
ment with the experimental measurements for binding of
thionine to CP-DNA, are given in Table 1.
The transition profiles and heat capacity for un-
bounded DNA duplex and bounded with thionine are
shown in Figure 2. Minor insignificant deviation at the
tail ends is primarily due to the presence of various dis-
ordered states and presence of short helical segments
found in the random coil states. Figure 2 A shows ex-
perimental and calculated transition curves for the duplex
in the absence of thionine and B shows the transition
when the duplex is saturated with thionine (thionine/
DNA = 0.4). As expected, a cooperative transition profile
is observed with calculated data. The conclusion deduced
from the theoretical data is consistent with the directly
measured binding enthalpy by Paul et al. [7] determined
through DSC.
Table 1. Transition parameters for thionine binding to CP-
DNA.
Parameters Unbounded
CP-DNA
CP-DNA saturated
with thionine
Tm (K) 345 351.5
∆H Kcal/M bp 3.06 × 103 3.24 × 103
σ 3 × 10–4 5 × 10–4
N 98 90
Ah 0 0
Ar 1 1
Half width (Exp.) 5 6.5
Half width (Theo.) 5 6.5
Sensitivity parameter (∆H/σ) 102 × 105 648 × 104
Figure 2. Heat capacity and transition profiles (inset) for
thionine bounded and unbounded CP-DNA. A: Unbounded
state; B: Bounded state at saturation. [(—) calculated and
(••••) experimental values].
3.2. Heat Capacity
The conformational and dynamical states of a macromo-
lecular system are characterized by heat capacity which
is second derivative of the free energy and has been cal-
culated by using Equation (14). These heat capacity
curves with λ-point anomaly are shown in Figure 2 along
with their transition profile. The theoretically obtained
heat capacity profiles agreed with the experimentally
reported ones and could be brought almost into coinci-
dence with the use of scaling factors, which is very close
to one in transition profiles and slightly higher for the
heat capacity curves. The sharpness of the transition can
be characterized by the half widths of the heat capacity
curves that are in good agreement in both experimental
and theoretical graphs.
4. Discussion
The present study concluded that the natural CP-DNA
molecule is an extremely co-operative structure and when
thionine bind to it the co-operativity is not so much dis-
turbed. Therefore, the amended Zimm and Bragg theory
(phase transitions theory) can be effectively applied to it.
It generates the experimental transition profile and λ-
point heat capacity anomaly successfully. These results
will allow us to assess the thermodynamic profile of the
binding process. Our theoretical studies of heterocyclic
aromatic molecules binding are being extended to other
synthetic and natural nucleic acids. The theoretical data
obtained also demonstrated that the binding of thionine
to CP-DN is an endothermic process and that this binding
increases the melting temperature of the duplex as sup-
ported by calorimetric measurement. The specific bind-
ing and intercalation of thionine with DNA have been
studied by using spectroscopic methods [13,17]. How-
ever, Paul and her coworkers used optical melting and
DSC techniques to understand the interaction of small
molecule, thionine, with double stranded deoxyribonu-
cleic acid, native CP-DNA [7]. The binding of thionine
stabilized CP-DNA and ΔTm value of about 6.3˚C was
obtained under saturating condition. Accordingly, we can
interpret our theoretical results in the context of the spe-
cific structural features of the complex as deduced from
their spectroscopic/DSC data. Inspection of Figures 2 A
and B reveals that the transition of the thionine-saturated
CP-DNA duplex is significantly broader than the transi-
tion of the thionine-free duplex. Thus, in addition to af-
fecting the transition enthalpy and the melting tempera-
ture, binding of heterocyclic aromatic molecules also
alters the nature of the transition as reflected by the in-
crease in transition width in experimental and calculated
(theoretical) both data. In recent years, an increased un-
derstanding of the role played by nucleic acids in bio-
logical systems made DNA an alternative candidate for

G. YUNUS ET AL.
102
the development of new drugs. The successful applica-
tions of molecular modeling in virtual ligand screening
and structure-based design of organic and inorganic mo-
lecules that target DNA are highlighted by Ma et al. [27].
The interactions of drugs and calf thymus DNA were
also investigated by using non-linear fit analysis [28].
Other recent literatures also reviewed that the study of
DNA interaction with a small molecules is of high inter-
est [7,29-32]. Thus, the present theoretical analysis can
be applied to understand bimolecular interaction and may
also be implicated to the process of drug development in
biomedical industries.
5. Acknowledgements
Technical assistance from Dr. Mohammed Kuddus, De-
partment of Biotechnology, Integral University, Lucknow
is gratefully acknowledged.
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