Stretching Single Stranded DNA: Cite This: Soft Matter, 2011, 7, 4595

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Stretching single stranded DNA

Sanjay Kumar* and Garima Mishra
Received 6th October 2010, Accepted 13th January 2011
DOI: 10.1039/c0sm01110j
Recently, single molecule force spectroscopy experiments provided much important information about
the elastic properties of a single stranded DNA. Theoretical efforts, which followed these experiments
could not provide satisfactory explanation for some of the observed results. For example, a decrease in
the extension with temperature at high force, multi step transition in the force extension curve of
poly(dA), etc. need further attention. In this brief review, we discuss a few of these experiments and
illustrate that lattice models developed in the framework of statistical mechanics may describe some of
the observed features. We also propose an experimental protocol, which may enable us to observe
re-entrance, a long standing issue related to the force induced transitions of biopolymers.
I.
Introduction
The last ten years have witnessed a revolution in single molecule

force spectroscopy (SMFS) experiments involving the manipulation of DNA.17 This interest has been fueled on the one hand
by the desire to understand the fundamental mechanisms at play
in the processes like transcription and replication, and on the
other hand by the development of revolutionary techniques,
which permit manipulation of these molecules.812 These experiments provide a deeper insight into the strength of the forces
driving these biological processes8,9 and help to determine
various biological interactions involved in the mechanical
stability of DNA.14
At equilibrium, a double stranded DNA (dsDNA) will separate, when the free energy of the separated single stranded DNA
(ssDNA) is lower than that of the dsDNA.1315 In most of the
biochemical studies of DNA separation, with the rise of
temperature (T), base pairs open and bubbles form. At a certain
temperature, the number of intact base pairs drops abruptly and
two strands get separated. This process is termed as DNA
melting or thermal denaturation.16 However, in vivo, DNA
separation is not thermally driven, rather mediated by the
enzymes and other proteins,13 which exert the force of the order
of pN on the selected portion of the DNA.17 It is now possible to
separate a dsDNA with a force applied solely at one end instead
of varying the temperature or pH of the solvent.8,9 The force (F)
required to separate DNA is found to be z15 pN.8,9 A large
number of theoretical and numerical attempts1827 have been
made to gain further insight into the mechanism of DNA
opening.
One of the major results from these studies was the prediction
of re-entrance in the low temperature region of the force
Department of Physics, Banaras Hindu University, Varanasi, 221 005,

India
This journal is The Royal Society of Chemistry 2011
temperature diagram, where the dsDNA goes from the unzipped

state to the zipped state and again to the unzipped state with the
rise in the temperature at a constant force. It is now well established that the observed re-entrance is due to the ground state
entropy of the zipped state. Using the phenomenological argument,23,24 it was shown that the critical force for the unzipping
increases with temperature up to a certain temperature and then
it starts decreasing. To observe the re-entrance in vitro, temperature as well as the ground state entropy of the system should be
large.2124 Notably, now the theoretical predictions of re-entrance
are not only confined to the DNA but also for other bio-polymers.2832 Surprisingly, such re-entrance remained elusive so far
in the experimental studies. The reason for this may be that for
the DNA or protein, the ground state entropy is not so large and
thus such effect has not been seen in vitro so far.
Early studies based on the SMFS experiments also revealed the
unusual elastic properties of DNA.16 It was found that the
dsDNA is a semi-flexible chain and the force extension (Fx)
curve can nicely be reproduced by the worm like chain (WLC)
model.33 Whereas, the ssDNA behaves like a flexible polymer
chain and can be described by the freely jointed chain (FJC)
model.34,35 Because of the intra-strand electrostatic repulsions,
the ssDNA is stiff over the short length scales (35 bases)
compared to the dsDNA, where it is stiff over a larger length
scale (50 to 100 base pairs). The dsDNA shows the entropic
elasticity in the range 0.01 to 10 pN.5 At higher forces (10
60 pN), the WLC model can describe the experimentally
observed Fx curves. In the high force regime (65 pN), it was
found that the dsDNA molecule can be overstretched about 1.7
times of the B-form contour length and a phase transition occurs
from the B-form to a stretched or S-form.2,5 An explanation of
this regime is attributed to the short range nature of base pair
stacking interactions. At high forces, the stacking potential can
no longer stabilize the B-form configuration of the dsDNA and
the stacked helical pattern becomes distorted. Recently, van
Soft Matter, 2011, 7, 45954605 | 4595
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Mameren et al.38 have studied DNA stretching with or without

DNA binding ligands and demonstrated that the overstretching
comprises a gradual conversion from dsDNA to ssDNA and it
should be interpreted in terms of DNA melting. Although, there
are many good reviews on the subject,2,36,37 it appears there are
some intriguing issues related to the S-form and related structural transitions.39
Efforts have now shifted to the experimental studies on
molecular conformations of ssDNA or RNA molecules. Interestingly, a ssDNA has twice the contour length per base
compared to the dsDNA, because the helical backbone of the
ssDNA extends about 0.8 nm per base compared to 0.3 nm per
base of dsDNA. As a linear chain of nucleotides with a thin
diameter and a large flexibility, the ssDNA is more contractile
than the dsDNA at low forces, but it can be stretched to a greater
length at high forces because of the absence of the helix.2,40 The
most striking difference between dsDNA and ssDNA is that
a ssDNA can stick (form hairpins) to itself by base pairing and
stacking interactions between bases along the same molecule.
The comparison of the force-extension curves with theoretical
predictions over the entire force range including the entropic
regime (low force) as well as the energetic regime (high force) is
still a challenge.
In this brief review, we are going to address some of the recent
works on the ssDNA,4143 which require further attention in the
frame work of statistical mechanics to have a better understanding about the force induced transitions. Section II reviews
some of these results seen in the recent experiments. In section
III, we review the latest developments in the lattice models of
DNA, which incorporate the excluded volume effect, non-native
base pairing interaction, stacking interaction and base direction
in its description.24,4446 We also discuss the exact enumeration
analysis to calculate the partition function and the thermodynamic variables of the system.4749 Using the approach described
in section III, we compare the theoretical findings of DNA
stretching based on the lattice models with the experimental
results in section IV. We illustrate when and how the theoretical
descriptions of the model fails and further refinements in the
model are essential to explain the experimental observations.
Section V describes the effect of temperature on the ssDNA in
the presence of a force. Here, we show that in the constant force
ensemble the reaction coordinate has a non-monotonic behavior.
Based on the finite-size chain analysis, it was shown that at the
low force, the reaction coordinate increases with temperature,
while at high force, it decreases with temperature. This is in
accordance with the experiment43 described in Section II. Section
VI dwells with an experimental protocol to observe the reentrance50 which remains elusive so far in vitro. The paper ends
with a brief discussion in Section VII.
II. Brief overview of present status

The ssDNA structure is very sensitive to the composition and
concentration of ions. This was seen in the force-extension curves
for the ssDNA.37 Using the approach developed for the worm
like poly-electrolytes, the FJC and WLC models5 were used to
explain the force-extension curves under different ionic strengths.
In a 150 mM NaCl solution, the force-extension curve of
a ssDNA melted from the l-phage DNA can be fitted with a FJC
4596 | Soft Matter, 2011, 7, 45954605
model of Kuhn length 1.5 nm with an additional stretch

modulus.5 Interestingly, the theoretical description of the FJC
model fails in low (2 mM NaCl) and high (5 mM MgCl2) ionic
solutions.51 To explain the high concentration data, it was argued
that the secondary structures (hairpins) have formed, when
a ssDNA sticks to itself and its complementary bases form base
pairs, and consequently a larger force is required to pull the
ssDNA having such hairpins than expected from the FJC
model.35 Montaniri and Mezard have done a theoretical analysis
of the elasticity of a polymer chain with hairpins as secondary
structures.35 The model developed by them reproduces the
experimental Fx curve measured on ssDNA chains, whose
nucleotide bases are arranged in a relatively random order. The
force-induced transition in the hairpin is found to be of
the second order and characterized by a gradual decrease in the
number of base pairs as the external force is increased.
Zhou et al.52,53 studied the secondary structure formation of
the ssDNA (or RNA) both analytically as well as by the Monte
Carlo simulations. In the modeling work, the following three
major interactions were considered: base-pair hydrogen bonds,
base-pair stacking interactions, and electrostatic interactions
along the nucleotide chains. Their work demonstrated the
importance of base-pair stacking interactions in governing the
cooperativity of the RNA/ssDNA coil-hairpin transition under
high salt conditions. Under low salt conditions, the electrostatic
repulsive interaction becomes very important. Based on their
studies, they could show that the force induced transition is
continuous from the hairpin-I (base stacking interaction is small)
to the coil, while a first order for the hairpin-II, where the base
stacking interaction is large. Hugel et al.54 studied three different
chains namely ssDNA, poly vinylamine and peptide at very high
force (2 nN). At such a high force conformational entropy does
not play a significant role, therefore, zero temperature ab initio
calculation can be compared with the experimental results. It was
shown that with a single parameter (the contour length L0), one
can obtain different elastic constants, which describes the forceextension curves quite well at high force.
New challenges have emerged when the semi-microscopic
changes in the monomer (nucleotide) are found to influence the
elastic property of the nucleic acids. Attempts have been made to
monitor the Fx curve42,43 of RNA and ssDNA consisting of only
one type of nucleotide. It was found that the elastic properties of
ssDNA made up with adenine (poly(dA)) are significantly
different from the thymine (poly(dT)) or uracil (poly(rU)). The
Fx curve for poly(rU) (Fig. 1) show the effect of the entropic
elasticity, whereas the poly(rA) exhibits a plateau in the Fx
curve,42 which were found to be absent in the earlier experiments.2,34,55 A plateau obtained in case of a ssRNA (poly(rA))
has been explained on the basis of seven parameters42 in the
Zimm-Bragg model.56 The qualitative understanding of the
plateau has been achieved in terms of the unwinding of helical
structure of poly(rA) arising due to the base stacking. This
transition appears to be weakly cooperative, but needs further
attention from the statistical mechanics point of view.42,57,58
In another attempt, Ke et al.43 studied the elastic properties of
ssDNA and the Fx curves of poly(dA) and poly(dT) (Fig. 2) and
found the existence of multi step plateau in the case of poly(dA).
The first plateau occurs at a force 23 1 pN and overstretched
the nucleotide by 74% which has been predicted by the model
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Fig. 1 Forceextension curves for poly(A) (solid square) and poly(C)

(open circle). Solid lines are fit from the equation given in Ref. [42]. Force
extension curve for poly(U) is also shown (open triangle). It is evident
from this that poly(U) shows the entropic response, whereas poly(A) and
poly(C) show the existence of plateau. For detail, see Ref. [42].
proposed by Buhot and Halperin.57 This was also seen in the case
of a homo polymeric RNA42 as discussed above. Moreover, the
second plateau, which occurs at a force 113 1 pN and overstretches ssDNA by an additional 16%43 was not predicted by the
model proposed by Buhot and Halperin.57 Though, Ke et al.
conjectured that the second plateau is associated with the
Fig. 2 (a) Forceextension curves for poly(dT) of three different lengths,

(b) comparison between poly(dA) and poly(dT) on a normalized extension basis. It is clear that poly(dT) shows the entropic response, whereas
poly(dA) shows the two plateaus. For detail see Ref. [43].
structural transition, but high level ab initio quantum mechanical

calculation43,59 did not support it.
In many biological processes, there is a large conformational
change and temperature plays a crucial role. Therefore, efforts of
SMFS experiments have been shifted to study the effect of
temperature on these processes keeping the force constant.11,41,60
Danilowicz et al.41 studied the elastic properties of the ssDNA
and showed that the temperature has significant impact on the
force-extension curve. In the low force regime, they found that
the extension increases with temperature (Fig. 3). By changing
the solvent condition, they could show that the increase in the
extension is due to the disruption of hairpins. Using the Poland
Scheraga (PS) model of double-stranded DNA (dsDNA)61,62 and
the modified freely jointed chain model (mFJC)34,35,53 of a polymer, they could nicely represent the forceextension curves in the
low force regime. For the higher forces, none of these models
could explain the outcome of their experiment, where the
extension decreases abruptly with the rise of the temperature and
it appears that there is no clear understanding about it. It was
suggested that the observed decrease in the extension may be
because of the sequence dependent secondary structures.41
III.
Theoretical modeling of ssDNA
In this section, we are going to discuss the lattice models of DNA,

which have been recently used to describe some of the features of
the force induced transitions related to ssDNA.24,4446 The model
built on the extension of the self-avoiding-walks model of polymers,63 which takes care of the excluded volume effect, an
Fig. 3 Figure shows the extension vs. temperature for several beads at
constant force. Extension data at several forces and increasing temperature from bottom to top: 2, 3, 6, 10, and 12.5 pN (black solid symbols); 2
and 6 pN and decreasing temperature (black empty triangles); 3 pN and
increasing temperature in 0.75 M NaCl- phosphate buffer pH 7.4 (purple
squares); theoretical predictions from two state models are shown with
dotted gray lines obtained from eqn (1) of Ref. [41]and blue and red
dashed lines correspond to the fits that include hairpins in the theoretical
calculations. For detail see Ref. [41].
Soft Matter, 2011, 7, 45954605 | 4597
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important shortcoming of the models (e.g. FJC, WLC) based on

the random walk. The model has successfully described many
features of polymer49,6367 and can incorporate semi-microscopic
fetaures of ssDNA24,4446 in addition to the excluded volume e.g.
the directional nature of the hydrogen bond, non-native base
pairing and the most important configurational entropy, which
gives rise the existence of the stretched state.
In this model, a walk of N steps (N + 1 vertices) on a square
lattice (2D) and cubic lattice (3D) has been considered. Two
vertices (nucleotides) are connected through a covalent bond. A
step of the walk may represent this bond or the persistent length
(consisting of few monomers) of a polymer chain depending on
the choice of the problem. With each step, a base is attached
(Fig. 4) which has a direction. The repulsion between monomers
at short distances (i.e. excluded volume) is taken into account by
the condition of self-avoidance.
The base pairing interaction can take place only when the
nearest neighbour lattice bonds are parallel and the complementary bases associated with the lattice bonds are pointing towards
each other (Fig. 4). The nearest neighbor interaction mimics the
short range nature of the hydrogen bonds and an energy (3p < 0) is
gained with the formation of each base pair. When the direction of
two complementary bases (nucleotides) of neighboring parallel
lattice bonds are not pointing to each other as shown in Fig. 4, they
do not form a base pair. The model can take care of the non-native
base pairing with a condition that a base can pair with at most one
of its complementary bases. Such a condition has been incorporated by considering the native interaction in the models based on
the PolandScheraga model, and hence, precluding the existence
of the secondary structure of ssDNA.
In order to study the consequences of the orientation of bases,
we allow bases to orient around the bonds in the model.40 If two
adjacent bases of the strand are in the same direction (Fig. 4), it
has been referred to as stacked bases and an attractive interaction
has been associated with it. In contrary to a continuum model,
where stacking can occur in all possible directions, on a cubic
lattice, bases can stack only in four possible directions. The
model is rich enough to include the effect of the inter stacking
interaction in its description. For this, we associate an attractive
energy term (3inter) with the cross stacked bases (nearest

neighbor) pointing towards each other (Fig. 4).
The thermodynamic properties associated with the force
induced transitions related to ssDNA are obtained from the
partition function, which can be written as a sum over all possible
configurations
X
ZN
CN1 ; N2 ; N3 ; xebN1 3p ebN2 3intra ebN3 3inter ebFx ; (1)
N1 ;N2 ;N3 ;x
where b 1/kBT. Here, onwards the Boltzmann constant kB is set

equal to 1, and hence, all the results are in the reduced unit.
C(N1,N2,N3,x) is the number of distinct conformations of walk of
length N, whose end points are at a distance x. N1, N2 and N3 are
the number of intact base pairs, intra stacked bases and inter
stacked bases, respectively. It should be noted that the value of
3p, 3intra and 3inter depends on the participating nucleotides and
their relative value can be obtained from Ref. [68]. The energy
arising due to the applied force F is Fx.63 The time required to
enumerate these conformations increases as mNzN because of the
extra degree of freedom associated with the base orientation (z
2 for the square lattice and z 4 for the cubic lattice).49,46 Here
m is the connectivity constant of the lattice. The model can also
take care of the steric effect among adjacent bases and conformations like the one shown in Fig .4b have not been included in
the partition function defined in eqn (1).
IV.
Forceextension curve of SSDNA
The model introduced in the previous section is a coarse grained

one, where the distinction among nucleotides A, T, G and C can
be incorporated. Moreover, the model includes the orientation of
bases, which allows us to study the effect of stacking. It is known
that intra-base stacking is the strongest among adenine and the
weakest among thymine and uracil.69 As a result, the intra base
stacking favors a parallel orientation of consecutive bases in
poly(A), but not in poly(dT) or poly(rU).40,70 The inter stacking
energy, which is quite low in comparison to intra stacking
energy68 may not play a crucial role in case of stretching.
Therefore, its contribution in the partition function has not been
taken into account. The issue of cooperativity can also be studied
exactly in this model by associating a cooperativity factor
(s eb3 ) between the stacked and the unstacked domain.56 Here
3w > 0 is the wall energy associated with the wall between the
stacked and the unstacked domains. Since 3intra < 0, therefore,
the sign appearing before this term in eqn (1) becomes positive.
The partition function defined in eqn (1) reduces to the following
equation for the poly nucleotides (3p 0)
X
CN2 ; N4 ; xebN2 3intra ebN4 3w ebFx ;
(2)
ZN
w
N2 ;N4 ;x
Fig. 4 The schematic representation of ssDNA of an arbitrary sequence.

Apart from the base pairing interaction ep (shown under ellipse), two
types of stacking interaction may arise, namely inter strand shown by the
solid line and intra-strand shown by the dashed line. Figure also shows
that the complementary nucleotides are the nearest neighbor but direction of bases are not towards each other, and hence, do not form the base
pairs. In (b), we also show the steric repulsion (shown under circle)
among the adjacent bases. The small black circle indicates that one end of
the ssDNA is kept fixed, while a force is applied at the other end (light
blue circle).
4598 | Soft Matter, 2011, 7, 45954605
where N4 is the number of walls between a stacked and an

unstacked domains. The quantity of experimental interest i.e the
reaction co-ordinate2,57 (in this case the end to end distance) can
be obtained from the expression
1 X
xCN2 ; N4 ; xebN2 3intra ebN4 3w ebFx :
(3)
hxi
ZN N2 ;N4 ;x
In absence of the stacking interaction and the cooperative
factor (3intra 0 and 3w 0), Fig. 5a shows the entropic response
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of the chain (consisting of 21 steps on the square lattice), which

has been observed in case of poly(rU) (or poly(dT)).42,43 In
Fig. 5a, one can notice that the curve for 3intra s 0 shifts to the
right of 3intra 0. Moreover, to keep the extension say at 0.8, one
requires less force for 3intra s 0 as compared to 3intra 0. In
contrary, the experimental curve (Fig. 5b) obtained by
Seol et al.42 for poly(rA) (3intra s 0) shifts to the left of ploy(rU)
(3intra 0) and to keep the extension say 1200 nm, one requires
almost the double force than the poly(rU). This indicates that
apart from the stacking interaction and the cooperativity, there
must be some other mechanism involved in the elasticity of
poly(rA).
Buhot and Halperin proposed57 that the base stacking favors
the formation of helices. Thus, the effective end-to-end distance
(R0 ) decreases as shown in Fig. 6. In this case, the applied force
unwinds the helices as well as competes with the stacking energy.
Since the model has exact information about the number of
stacked bases (N2) participating in the formation of the helix,
therefore, the reduction in length can be calculated exactly.
Following the procedure adopted in Ref. [57], the reaction
coordinate x is reduced by a certain factor proportional to N2 i.e.
x0 x N2a. The value of proportionality constant a b/a z
and b 3.7 A.
42,57 Here
0.63 was obtained by setting a 5.9 A
a and b are the inter phosphate distance and rise in the length of
the helix per nucleotide respectively. The modified Fx curve,
with this constraint,46 has been shown in Fig. 5c. Surprisingly this
consideration not only shifts the curve to the left as seen in the
experiment (earlier shifting to the right in absence of helix), but
also qualitatively reproduces the F-x curve obtained by Seol
et al.42
In Fig. 5a, we show that the forceextension curve obtained by
using the cooperativity parameter s 0.51 and 3intra 0.6, which
overlaps with s 1.0 (no cooperativity) and 3intra 0.8.
Therefore, the stacking interaction reproduces the Fx curve for
the low cooperativity. In fact, the nature of the curve remains
almost the same up to s 0.71. This is in accordance with earlier
studies, where it was also found that the stacking decreases the
cooperativity of melting of the homo polymeric DNA71
When the cooperativity increases, the flatness of the curve
(Fig. 5c) also increases. The reduction in the reaction coordinate
(x0 x N2a) along with s modifies eqn (3), which gives rise to
such an effect. From Fig. 5c, it can be noted that the curve with
the cooperativity (s 0.51) crosses the curve without the
Fig. 5 (a) Forceextension curve for the model ssDNA (homosequence)

for different values of eintra. eintra 0 corresponds to poly(T) (or poly(U)),
which shows the entropic response.42,43 eintra s 0 represents the case (e.g.
adenine) where stacking plays a role in the formation of a helix; (b)
experimental Fx curve42 for the poly(rA) (filled square) and poly(rU)
(open circle). Here F is in pN. (c) Figure shows the Fx curve obtained
from the model which includes the formation of helix (dotted line). In (a)
and (c) force and extension are in the reduced unit.
Fig. 6 (a) The schematic representation of poly(T). (b) In the case of

poly(A), bases can stack and form a helix like structure. Inset shows the
base stacking for a specific segment; (c) shows the unwinding of the helix
where the consecutive phosphate distance remains the same; (d) here, the
chain is in the stretched state, where few bases are stacked. Flipping of
bases in the presence of high force shows the extension in the consecutive
phosphate i.e a0 > a.
cooperativity (s 1) at the extension (z0.7). This has been

identified as a crossover point, where the chain goes from the
extended to the stretched state.29
Existence of the second plateau (Fig. 7a) at higher forces as
seen in the case of poly(dA)43 requires further refinement in the
model. The sugar in nucleic acid is a furanose (5 atoms ring),
which plays a significant role in determining the flexibility of the
chain. It is known that the furanose ring is puckered rather than
planar. It may have one atoms displaced from the plane (the
envelope forms) or two (T-form). Since, it can be either up or
down with respect to the plane, therefore, there are 20 possible
distance
conformations.72 The two basic forms c30 endo (5.9 A
0

between neighboring phosphates) and c2 endo (7.0 A distance
between neighboring phosphates) characterize two distinctly
different families of nucleic acid structures. The reorientation of
bases at high force may lead to a conformational transition in the
Fig. 7 (a) Experimental forceextension curve43 for the poly(dT)

[dotted] and poly(dA) [dashed] of ssDNA. Solid line is for the poly(dA)
using the mFJC2; (b) figure shows the forceextension curve, where the
formation of helix as well as increase in the consecutive phosphate
distance between bases has been taken into the consideration (force and
extension are in the reduced unit). One can see that inclusion of such
considerations qualitatively reproduces the forceextension curve
obtained by Ke et al.43 and exhibits the multi-step plateau.
Soft Matter, 2011, 7, 45954605 | 4599
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deoxyribofuranose rings from c30 endo pucker to c20 endo pucker

in a step like jump.72,73 If so, then it gives an additional extension
about 18% in the chain. However, 12 kcal mol1 energy difference between two states could not reveal, which conformation
(c30 endo or c20 endo) poly(dA) will take under equilibrium
condition.43
In order to see whether the second plateau is a result of the
structural transition, the number of unstacked bases has been
calculated exactly in the model, which may participate in this
transition. The reaction coordinate has been increased by
a factor proportional to the number of unstacked bases. The
proportionality constant for this case has been obtained from the
Ref. [72,73]. The modified Fx curve depicted in Fig. 7b shows
the multi step plateau, which is qualitatively similar to the
experimental one.43 This implies that further increase in the
extension (second plateau) is associated with the structural
transition. Moreover, curves for different values of s > 0.51
almost overlap with the curve for s 1, and hence, the transition
appears to be weakly cooperative.
In order to study the variation of stacked bases (N2) along the
chain, the probability distribution (P(N2)) of poly(dA) has been
calculated from the following expression (for s 1):
1 X
CN2 ; xebN2 3intra ebFx :
(4)
PN2
ZN x
In Fig. 8, the probability distribution for the stacked bases
P(N2) for the different values of force at a fixed temperature T
0.3 for the poly(dA) has been shown. The maxima of P(N2) for
F 0 occurs at N2 z 17. This represents the situation, where
most of the bases are stacked (helix) and domains are randomly
oriented. Slight increase in the force aligns the helix along the
force direction and thus the number of stacked bases increases
slightly. This can be seen from Fig. 8, where the maxima of P(N2)
shifts toward the right. For low forces, thermal fluctuations are
too weak to unstack the bases in the strand. From the Fig. 8, one
can see that there is an emergence of a new peak around the value
N2 8 and decrease in the peak heights around N2 17 at the
intermediate forces (F 0.2 to 0.365). The first plateau took
place at F 0.365 as shown in Fig. 7. At this force, the height of
both peaks are found to be equal. Two peaks of equal height in
the probability distribution curve show the signature of coexistence of two phases (helix and coil). This is analogous to the
liquidgas transition. Here, the force represents the pressure and
the extension is analogous to the volume.58 In this region, the
number of stacked bases decreases, which reflects the unwinding
of the helix. This gives relative extension (70%) in the backbone. Further rise in the force (above F 0.5) shifts the maxima
of the distribution curve towards the left. This reflects that the
number of stacked bases in the stretched state decreases gradually and gives additional increase in the extension, which is about
16% as shown in Fig. 7.
It may be important to point out that Ke et al. conjectured that
the second plateau is associated with the structural transition,72,73
but high level ab initio quantum mechanical calculation43 did not
support it. In order to resolve the issue associated with the
structural transition in poly(dA), it is essential to calculate the
change in the energy associated with this transition. Ke et al.
obtained the total energy (3.6 0.2 kcal mol1 per base) from the
area under the Fx curve for the adenine (Fig. 7a) and interpreted it as base stacking energy. In fact the total area under the
curve (poly(dA)) should be attributed to entropic, enthalpic,
structural and elastic contribution. However, in case of the Fx
curve of thymine (poly(dT)), the contributions come from the
entropic and elastic part only. Therefore, at low force (neglecting
the elastic contribution) one can get the rough estimate of the
enthalpic contribution (0.6 kcal mol1 per base) associated with
the coil-helix transition corresponding to the first plateau. This
value is in agreement with the known values available in the
literature.69 At high force, the elastic contribution for the
thymine is different than the adenine, and hence, one cannot get
the energy required for the structural transition from the same
curves. It may be visualized that the area under the thymine curve
is more than the adenine. By using the same persistence length for
the adenine,55 one can get the Fx curve from the mFJC2,41 that
contains only the entropic and elastic contributions, which is
shown in Fig. 7a. The energy (1.2 0.2 kcal mol1 per base)
associated with the structural transition above the extension 0.58
has been obtained by subtracting the mFJC curve from the
experimental Fx curve.46 This value is in excellent agreement
with the quantum calculation.59
V. Effect of temperature
Fig. 8 Figure shows the probability distribution curves for the adenine.
At low forces most of the bases are stacked and curve peaks around N2
1618. Coexistence of two peaks at force (F 0.365) shows the signature
of first order phase transition. Above the force F 0.5, the stacked bases
start decreasing gradually.
4600 | Soft Matter, 2011, 7, 45954605
In order to see whether the abrupt decrease in the extension is

a sequence dependent effect,41 we consider two conformational
possibilities of a ssDNA in the constant force ensemble in 3D
(Fig. 9). In the first case, we consider the first half of the chain,
which is complementary to the other half of the chain. The
ground state of this will be the zipped state and may be viewed as
a dsDNA.23,24,45 In the second case, we consider a hairpin, consisting of a stem and a loop, where the first few bases are
complementary to the last few bases (form a stem) and remaining
bases are non-complementary (form a loop). To keep 50 -30 base
pairing along the chain, bases are not allowed to flip (for
simplification).
Moreover, the intra- and inter- strand interactions have not
been considered explicitly here because of the following two
reasons: (i) these interactions for the homosequence can be
absorbed in the base pairing interactions and thus 3p may be
View Article Online
Fig. 10 Forcetemperature diagram for (a) the zipped DNA and (b) for
the DNA hairpin. Solid circles show the crossover regime.
Fig. 9 The schematic representation of a ssDNA forming (a) the zipped
conformation (dsDNA). In this case half of the strand is of A type
nucleotides and other half of strands consist of complementary nucleotide T. (b) A hairpin structure of stems of 3 bases. (c) Shows that by
application of a force applied to the one end, the system undergoes from
zipped or hairpin state to the extended state.
regarded as the effective base pairing interaction instead of the

hydrogen bonding between complementary nucleotides. (ii)
Relative magnitude of the inter strand interaction (may be
important in case of hairpin) is quite less compare to the base
pairing interaction except for GG.68 The partition function
defined in eqn (1) may be written as
X
ZN
CN1 ; xebN1 3p ebFx :
(5)
N1 ;x
Although no true phase transition can occur in the finite-size

single molecule experiments, the phase transition observed in
SMFS experiments may be considered as real, if the length of the
chain exceeds the characteristic correlation lengths. A sudden
change in the appropriate average (in this case number of base
pairs) may be used to obtain the different phases in the phase
diagram.29,44 The thermodynamic limit may be achieved by using
the extrapolation technique developed in Ref. 49. For example,
the phase diagrams obtained for the partial-directed self-avoiding walks (PDSAWs) are found to be in an excellent agreement
with the exact values27 and the qualitative nature remains the
same. It was shown that the values obtained from the fluctuation
in non-bonded monomers of finite size are also in quantitative
agreement (within 0.01) with the exact values.27 In view of
finite-size experiments, one chooses this technique, which
provides the complete state diagram at all temperatures and
forces. The forcetemperature diagrams of the ssDNA which
forms the zipped and the hairpin structures are shown in Fig. 10.
It can be seen from these plots that the unzipping force decreases
with the rise of temperature. Moreover, it also shows the reentrance in the model system. Using the phenomenological
argument,23,24 it was shown that the critical force for the unzipping is F 3 + Ts and the slope of the phase boundary (zipped
unzipped) at very low temperature in the force-temperature plane
dF
is
s. Here, s is the entropy per base of the DNA. In order to
dT
see the re-entrance in vitro, T as well as s (ground state entropy)
should be large. In the next section, we shall show the hairpin
may be an ideal candidate and discuss the protocol50 to observe
the re-entrance in vitro.
Here, we shall discuss the issue related to the decrease in the

extension with temperature. The average extension may be
obtained from the relation
1X
\x.
CN1 ; xxe3p =kB T N1 eF=kB T x :
(6)
Z N1 ;x
In Fig. 11, variation of the extension with the applied force for
the zipped and the hairpin situation at various temperatures have
been shown. It can be seen from these plots that the extension
increases with the applied force. This is in agreement with the
experiment41 discussed in Section II and qualitative understanding is known in terms of dissociation of base pairs. In the
constant temperature ensemble, by varying the force, one can go
from the zipped state or the hairpin to the extended state. With
further rise of the force, one finds the stretched state i.e. the
extension approaches the contour length of the ssDNA as seen in
the case of stretching of polymers.63 For a wide temperature
range, one can notice that these curves cross at a critical extension Lcross. Above this length the applied force increases with
temperature.29 In other words, to keep the extension constant,
one has to apply more force because the applied force competes
with the entropy of the chain.
In order to see the effect of temperature in a constant force
ensemble, we plot the extension vs. temperature curves in Fig. 12.
At low force, the extension increases with the temperature and
the chain acquires the conformation of the extended state. At
high force and low temperature, the system attains the stretched
state and it remains stretched up to a certain temperature. As
Fig. 11 The forceextension curves at different T (a) for the zipped state
and (b) for the DNA hairpin. One can see that the extension is
approaching to the contour length, when the force is varied. Y-axis scaled
to length.
Soft Matter, 2011, 7, 45954605 | 4601
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temperature increases, the applied force is not enough to hold the

stretched state and the extension falls sharply to the extended
state due to the increased contribution of entropy.
In order to understand the role of sequence, we plot the
extension vs. temperature curve (Fig. 13) for a situation where
the base-pairing energy in the partition function for one case is
set equal to 0. This is identical to a non-interacting linear polymer chain in a good solvent. It is surprising to see that all these
curves have similar behavior at high T indicating that chain is in
the extended state. However, the slope of the fall in extension
depends on the number of base pairs N1. It is pertinent to
mention here that at low temperatures, if formation of basepairing is possible, the system may again go to the zipped state as
predicted by re-entrance. Since in the experiment, possibility of
forming hairpin is suppressed by the solvent condition, the
observed decrease is solely due to the entropy.
In order to rule out that the observed decrease in the extension
is not a finite size effect, we revisited the unfolding of biopolymers, where the data of 55 steps in 2D (sufficiently long) allowed
us to settle this issue.29 In Fig. 14a, we plot the average extension
with temperature for a non-interacting polymer (in this case nonbonded nearest neighbor N1 0) and interacting polymer (N1 z
N). For both cases, we find the similar behavior that the extension decreases with temperature at high force. This clearly shows
that the sequence does not play any role as far as decrease in the
extension is concerned. We note that for the interacting polymer,
the fall is sharper than the non-interacting case. In Fig.14b, we
plot the <x>/N with N for different values of N. The collapse of
the curves of various lengths of the polymer chain at low
temperatures indicates that the chain is in the stretched state
and the observed decrease is not a genuine phase transition but
a crossover effect.45
VI. Protocol to observe re-entrance

One of the issue which warrants further attention from the
experiment point of view is the observation of re-entrance in
vitro. It has not been observed so far because it has been
attributed as low temperature phenomena, where most of the
solvents would freeze, precluding any unzipping experiment. It
may be recalled that temperature used in Section III is not a real
temperature (T*) but the reduced temperature (T) which is given
Fig. 12 Same as Fig. 11 but at different F. (a) For the zipped state and
(b) for the DNA hairpin. The abrupt decrease in the extension is obvious
from these plots.
4602 | Soft Matter, 2011, 7, 45954605
Fig. 13 Comparison of the extension vs. temperature curves with base

pairing and without base-pairing. For the zipped state the number of base
pair is N/2 while for hairpin it is 3. N1 0 corresponds to the noninteracting case.
by the relation T
3p T
. Where 3p is the effective base pairing
k
energy.
The important inferences that can be drawn from Section II
and VI pertain to (i) the ideal candidate to observe re-entrance in
vitro should be a single stranded oligonucleotide (a few bases of
both ends are complimentary to each other) which forms
a hairpin structure consisting of a stem (AT or CG) and a loop
(C or G for AT and A or T for CG).50,69,74 In this case, the
reaction co-ordinate (end-to-end distance) will exhibit a large
conformational change indicating the formation/disruption of
the hairpin in comparison to the l-phage DNA. Moreover, the
ground state entropy of the system will be large due to the
increased contribution from the loop. (ii) The reduced temperature of the system may be decreased or increased by changing the
concentration of glyoxal in the solvent, keeping the real
temperature fixed.34,41,50 It is to be noted that the solvent glyoxal
used in the above experiments reacts with DNA. It introduces an
additional ring to the G-base (to form a tricyclic compound i.e.
glyoxaldG), thereby sterically preventing G-C base pair reannealing.7577 Therefore, it may not be an ideal solvent to use as
a denaturating solvent to observe the re-entrance.
There are many solvents which can be used as denaturating
agents (e.g. urea, formamide, formaldehyde, ethidium bromide
etc.) to shift the DNA melting curve to lower temperatures.7881
We suggest to use formamide50 which forms hydrogen bonds
Fig. 14 (a) Extension vs. temperature curves in 2D for the interacting

and non-interacting walks of chain length 55 at different F. The sharp fall
indicates the effect of pairing interaction among the non-bonded
monomers. (b) Normalized extension vs. temperature curves for different
length (N 25, 30, 35, 40, 45, 50 and 55) at F 1.2. The collapse of data
at low temperature indicates that the chain is in the stretched state.
View Article Online
with the bases that replace the native ones and hence disrupts the
base pairing of DNA. It has been seen experimentally that the
melting temperature decreases linearly with the concentration.
The relation which has been used quite frequently to determine
the melting temperature is
Tm 81.5 + 16.6logM + 41(xG + xC) 500/L 0.62f
(7)
where M is the molar concentration of monovalent cations, xG

and xC are the mole fractions of G and C in the oligo, L is the
shortest strand in the stem and f is the molar concentration of
formamide.78,82 In fact each % of change in concentration reduces
the melting temperature by 0.6 degree. The major advantage of
this equation is that it includes the adjustment of salt and
formamide. Moreover, for the Molecular Beacon, the melting
temperature is about 40 C which can further be lowered by
changing the loop length.69,74 For a given loop length, by
adjusting formamide concentration, the melting temperature
may be brought well below the room temperature.
In the following, we propose the experimental protocol,50
which may be used for the detection for re-entrance. The
experimental setup used by Danilowicz et al.41 is the starting
point but instead of l-DNA, we propose to use Molecular
Beacon in the presence of formamide that forms a hairpin
structure.69,74 From the polymer theory, we know that a polymer
chain will be in either a closed state (hairpin) or a swollen state
(coil) depending upon temperature.63 In the closed state (low
temperatures), the average end-to-distance R will be nearly equal
to zero. At high temperatures, hRi scales as Nn with n 3/(d + 2),
where n is the end-to-end distance exponent. In the observed
experiment by varying the force, polymer chain acquires the
conformation of a stretched state. Hence force induces a new
stretched state which is otherwise not accessible and with the
rise of temperature, system attains the extended state.
In presence the of formamide, Molecular Beacon will attain
the stretched state at much lower temperatures than 40 C as
observed in the absence of formamide.69,74 Since in this region
(stretched state) stretching force increases with temperature
(upper line shown by solid circle in Fig. 15a), the required force
to keep the chain in the stretched state will also be less than 12.5
pN as seen in the experiment. If one now reduces the concentration of the formamide at that temperature and force, there will
be re-annealing of hydrogen bonds associated with complementary end bases of the Molecular Beacon. This corresponds to
the increase in the effective base pairing energy and thus the
reduced temperature and the force of the system will decrease in
order to keep the real temperature and the force fixed. Since the
applied force is not sufficient enough to keep Molecular Beacon
in the stretched state, the reduction in formamide concentration
will drive the system into the closed (hairpin) state at the same
temperature. In order to have higher closing rate (probability of
forming the hairpin), we propose to use a stem of CG and loop
made up of T. Since rate of closing is much higher than the rate of
opening (probability of opening), this will lead to the formation
of base-pairing resulting in a hairpin structure.69,74 If so then
there will be an abrupt decrease in the extension i.e. the reaction
co-ordinate will approach to zero. Now with the rise of the
temperature system will again attain the open state. It means that
in vitro, one would observe that the system is going to the closed
Fig. 15 (a)The forcetemperature diagram for the DNA hairpin. A

direct way to observe re-entrance is to follow a path I, II and III. Such
a path is difficult to achieve in vitro. Solid circles show the cross-over
region.45 By changing the concentration, one can decrease the effective
applied force and the reduced temperature, keeping the real temperature
and force fixed. Decrease in the reduced temperature also corresponds to
the decrease in the applied force, if the system is in the stretched state
(above the upper line shown by solid circles). An indirect way to observe
re-entrance is to follow the path I0 , II and III, in vitro. (b) Comparison of
the extension vs. temperature curves with base pairing (ep 1.5) and
without base-pairing (ep 0) at constant force 0.12. ep 1.3 corresponds
to a typical concentration of formamide, where the signature of reentrance can be seen. We also show the melting profile of hairpin in the
absence of force (ep 1.0 and F 0).
state (hairpin) from the open (stretched) and again to the open
(extended) state.
The model developed for hairpin in Section III and V may
describe the re-entrance. Here, we focus ourselves to study the
effect of concentration of formamide on the formation/disruption of hairpin. In order to do so, we vary the base pairing
interaction at constant temperature and force. 3p 0 will
correspond to oligonucleotide in the presence of formamide at
high concentration and the average elongation due to the force
can be found from the eqn (6). The phase diagram presented in
Fig. 15a is in the reduced unit, which shows a peak in force F at
temperature T z 0.09. To observe the re-entrance at a fixed force
say F 0.09, the direct way is to follow the path I, II and III by
varying the temperature.50 If we take base pairing energy equal to
0.198 1019 Joule per base then the melting takes place at
313 K. Values of T1 (open to closed) and T2 (closed to open) are
50 K and 175 K respectively. Such a low temperature and its
variation over a large interval are difficult to achieve in vitro. In
order to observe the re-entrance in vitro, we suggest to adopt an
indirect way (I0 , II and III), where by varying the solvent
concentration one can go from the open (I0 ) state to the closed
(II) keeping the real temperature fixed.
The observed decrease in extension (reaction co-ordinate)
shown in Fig. 15a with temperature is solely an entropic effect.
Since kB 1, we get F F*3p and T T*3p. The increase in 3p
means the decrease in formamide concentration and thereby
decreasing the value of the reduced temperature and the applied
force. If the applied force is high enough, the system will remain
in the stretched state. But if it is in proximity of the upper line,
increase in 3p (reduction in concentration of formamide) will lead
to the base pairing among the end bases in terms of the formation
of hairpin. This indeed we find in the extensiontemperature
curve shown in Fig. 15b, where the decrease in extension
approaches zero (showing the formation of hairpin) at
Soft Matter, 2011, 7, 45954605 | 4603
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a particular base-pairing interaction 3p 1.3. If we increase

temperature again, the system attains the open state as predicted
by the force-temperature diagram shown in Fig. 15a.
VII. Conclusions
In this brief review we have highlighted some of the relevant
issues related to the stretching of ssDNA. The simple lattice
model of ssDNA which includes excluded volume effect, nonnative base pairing and the directional nature of the hydrogen
bond along with the exact enumeration technique provide
qualitative understanding of the observed effects. The model
discussed above is a coarse grained, therefore, quantitative estimate of thermodynamic parameters are difficult to obtain.
Moreover, effect of salt concentration, pH of the solvent etc. are
experimental parameters, which have been generally ignored in
the description of coarse grained models. The model can be
parametrized,83 but there is not enough data so that the link
among concentration of the solvent, base pairing energy and
a force can be established. This requires additional experimental
and atomistic calculation at this moment to study the effect of
force in the presence of different solvent.
In spite of the simplicity involved in the lattice model, it
describes some of the observed features of the force induced
transitions. In the constant force ensemble, the extension has the
non-monotonic behaviour at low and high forces. At low force,
an increase in the extension is due to the dissociation of hairpins
which a ssDNA may form. Whereas at high force, the decrease is
due to the increased contribution of entropy of a chain, when
temperature is increased. The model study suggests that the slope
of the decrease may be increased either by changing the solvent
or changing the sequence of the chain. Moreover, in this force
range, a ssDNA may show the opening of helix if the sequence is
populated by adenine. At sufficiently high force, the modified
model does show the structural transition in the forceextension
curve of poly(A), which is qualitatively similar to the one seen in
the experiment.
It would be nice if future experiments could reveal the existence of re-entrance. In this context it is important to mention
here that sequence may play an important role. For example, if
one introduces the inter strand stacking energy 3inter along with
base pairing interaction 3p in eqn (6), the curve shifts towards the
higher temperature, but no qualitative change in the phase
diagram is observed. However, if inter strand stacking is high
(say loop is made up of G), then the slope of the forcetemperature diagram decreases and re-entrance becomes less prominent.
This is because of the fact that inter strand interaction reduces
the loop entropy. Hence the ideal candidate to observe reentrance is a hairpin whose stem is made up of GC and whose
loop consists of T.
Furthermore, the experiments of Seol et al.42 and Ke et al.43
suggest the formation of helix in adenine. It would be therefore
desirable to repeat the experiment of Danilowicz et al.41 with
poly(A) rich strand and poly(T) strand. The decrease in extension
with rise of temperature may shed important information about
the formation of the helix and therefore may lead to parametrization of base stacking interaction in the presence of force.
Lastly we would like to point out that the model proposed by
us is rich enough and can also include heterogeneity in its
4604 | Soft Matter, 2011, 7, 45954605
description. By replacing thymine (T) by uracil (U) and considering intra and inter strand interaction apart from the non-native
base pairing, the model may be extended to study the unfolding
of RNA,8486 which may considered as a step toward the
understanding of protein folding.
Acknowledgements
We would like to thank D. Giri, S. M. Bhattacharjee, P. E.
Marszalek and M. Prentiss for many helpful discussions.
Financial supports from the DST, New Delhi and CSIR, New
Delhi are gratefully acknowledged. We also thank the APS for
kindly permitting us to use the Fig.1, Fig.2 and Fig.3.
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