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Dna Breathing Dynamics in Terahertz Field

Dna Breathing Dynamics in Terahertz Field

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DNA Breathing Dynamics in the Presence of a Terahertz Field
B. S. Alexandrov,
1
V. Gelev,
2
A. R. Bishop,
1
A. Usheva,
2
and K. Ø. Rasmussen
1
1
Theoretical Division and Center for Nonlinear Studies,Los Alamos National Laboratory, Los Alamos, New Mexico 87545 
Harvard Medical School, Boston, Massachusetts 02215 
(Dated: October 28, 2009)We consider the influence of a terahertz field on the breathing dynamics of double-strandedDNA. We model the spontaneous formation of spatially localized openings of a damped and drivenDNA chain, and find that linear instabilities lead to dynamic dimerization, while true local strandseparations require a threshold amplitude mechanism. Based on our results we argue that a specificterahertz radiation exposure may significantly affect the natural dynamics of DNA, and therebyinfluence intricate molecular processes involved in gene expression and DNA replication.
Spectroscopic techniques in the terahertz range arecurrently emerging as new tools for the investigation of biological macromolecules [1]. In spite of the experimen-tal difficulties (caused by the water’s giant Debye dipolemoment, which leads to a substantial dielectric relax-ational loss in the THz range) a notable amount of re-search effort is being devoted to the development of so-phisticated THz bio-imaging[2]. Nevertheless, very littleis known about THz-radiation’s influence on biologicalsystems, and the mechanisms that govern this influence.The possibility that low frequency electromagnetic radi-ation may affect genetic material, enzymatic reactions,etc. was introduced long ago [3], and since then has beena subject of constant debate. The energy of such radia-tion is too low to directly disrupt any chemical bonds orcause electronic transitions. Only a resonance-type in-teraction might lead to an appreciable, biological effect.In biomolecules such interactions are possible throughthe ubiquitous hydrogen bonds that have energies in theTHz range. Numerous
in vivo
and
in vitro
experimentshave been conducted to clarify low frequency radiation’sability to cause biological effects, such as chromosomalaberration, genetic damage etc. The experimental stud-ies have been conducted under a variety of conditions,but mostly at frequencies below 0.01 THz, power below1
mW/cm
2
, and short exposure times. The data col-lected in these conditions led to mixed conclusions: somestudies reported significant genetic damages while oth-ers, although similar, showed none[4]. The major inter-national research project, ”THz-bridge”[5], which wasspecifically concerned with THz radiation genotoxicityconcluded that:
under some specific conditions of expo-sure, change in membrane permeability of liposomes wasdetected and an induction of genotoxicity was observeto occur in lymphocytes
. Hence, this project confirmedthe existence of THz genotoxicity, but it remains unclearunder which specific conditions such effects occur.Recent measurements confirm that only extended (6hours) exposure to a weak THz field can cause genomicinstability in human lymphocytes [6]. Independently, itwas reported that neurons exposed
in vitro
to powerfulTHz radiation (over 30
mW/cm
2
) cause infringement of the morphology of the cellular membranes and intracel-lular structures [7]. The same work also showed that atdecreasing power and/or at different frequencies the mor-phological changes do not occur. Recently, it was furtherpointed out that exposure to a low level THz radiationcan interfere with the protein-recognition processes[8].It was also shown that exposure of mice to 3.6 THz highpower (15
mW/cm
2
) radiation, for 30 min caused behav-ioral changes[9], while under short (5 min) exposure thechanges could not be detected. Thus the available ex-
FIG. 1: Spontaneous formation of a localized permanentopening in dsDNA in the presence of a THz field with ampli-tude
A
= 144 pN, and Ω = 2 and a spatial fluctuation withhigh amplitude (see text).
perimental data strongly suggest that THz-radiation canaffect biological function,
but only under specific condi-tions
, viz. high power, or/and extended exposure, or/andspecific THz frequency.The present work is devoted to developing a qualita-tive description of the existence of such THz effects. Weargue that the appropriate conditions correspond to ir-radiation parameters that assure the existence of linearand nonlinear resonances between DNA conformationaldynamics and THz field Fig.1.We will base our analysis on the Peyrard-Bishop-Dauxois (PBD) model of dsDNA[10], which is arguablythe most successful available model for describing thelocal DNA pairing/unpairing (breathing) dynamics[11].Of particular importance for the THz effect is our previ-ous demonstration of strong correlations between regula-tory activity, such as protein-DNA binding and transcrip-
arXiv:0910.5294v1 [physics.bio-ph] 28 Oct 2009
 
2tion, and the
equilibrium 
propensity of dsDNA for localstrand separation[12,13,14,15]. With this background it is natural to consider the influence of THz radiation ondsDNA dynamics within the PBD modeling framework.One complication is that the specific physical nature of the interactions between DNA and the THz electromag-netic field is not known in detail. However, given thesensitivity of THz radiation to the strand pairing stateof DNA[16], we will here simply augment the PBD toinclude a drive in the THz frequency range, without spec-ifying the precise nature of the underlying physical cou-pling. Since the wavelength of the THz field is largerthan 100
µm
and the characteristic size the investigateddsDNA sequences is less than 20
nm
it is reasonable toconsider an uniform THz field. In this fashion the breath-ing dynamics (represented by the normalized separation
y
n
of complementary bases) of the
n
’th base pair in thepresence of a monochromatic spatially homogeneous ex-ternal field is described by
m
¨
y
n
=
(
y
n
)
(
y
n
+1
,y
n
)
(
y
n
,y
n
1
)
mγ 
˙
y
n
+
A
cos(Ω
t
)
,
(1)where, the Morse potential
(
y
n
) =
D
n
(exp(
a
n
y
n
)
1)
2
represents the hydrogen bonding of the comple-mentary bases. The parameters
D
n
and
a
n
dependon the type of the base pair (A-T or G-C). Simi-larly,
(
y
n
,y
n
1
) =
12
χ
[
y
n
,y
n
1
](
y
n
y
n
1
)
2
with
χ
[
y
n
,y
n
1
] =
k
(1 +
ρ
exp(
β 
(
y
n
y
n
1
))) representsthe stacking energy between consecutive base pairs. Theterm
mγ 
˙
y
n
is the drag caused by the solvent while
A
cos(Ω
t
) is the (THz) drive. For simplicity, we con-sider here a homogeneous poly(A)[17]DNA moleculewith 64 base pairs. Our numerical simulations of this setof nonlinear coupled equations (using periodic bound-ary conditions) showed that the primary response of thesystem is spatially homogeneous (Fig.1the first 40
ps
).However, we observed that a presence of fluctuations maylead to the creation of persistent spatially localized open-ings of the double-stranded molecule, Fig.1. Because,such openings (bubbles) are known to functionally affectdsDNA we focus here on characterizing the conditionsunder which these states appear.Since, the primary response of of the driven system isspatially uniform it can be understood in terms of a singleclassical damped and driven Morse oscillator. Such sys-tems have been studied quite extensively in many othercontexts[18], and are known to display rich dynamicalbehavior including limit cycles, period-doubling bifurca-tions etc. An illustration of this is shown in Fig.2,A,for our system parameters, in terms of the Poincar´e sec-tion ˙
y
n
(
t
=
mT 
), where
= 2
π/
Ω, versus the driv-ing frequency Ω for several integer values of 
m
. Feigen-baum’s period-doubling route to chaos is clearly seen inthis figure, which demonstrates that this system’s maininstability mechanism is through period-doubling. As
FIG. 2: A) Bifurcation diagram for a poly(A) molecule inan external THz field with amplitude
A
= 144 pN. B) Theinstability curves for wave vector
k
= 0 (solid curve) and
k
=
π
(dashed curve) are plotted. On the vertical axis is theamplitude of the external field, and on the horizontal axis isthe frequency Ω of the THz field.
described earlier, our interest is to investigate whetherthe presences of a THz field can lead to the creation of spatially localized unbinding of the DNA double-strand.Such states are most easily created in connection with theperiod-doubling events, as a result of a spatially inhomo-geneous perturbation. In order to investigate this phe-nomenon we adopt a method developed in Ref. [19]. Inthis work the linear stability analysis (based on the Flo-quet theorem) of a single Morse oscillator was performed,and it was shown that in a rotating-wave approximation[20] the dynamics ensuing from a given perturbation isgoverned by the extended Hill equation. The stabilityanalysis of the Hill equation has been developed by Ince[21] based on his extension of the Whittaker’s methodof solving Mathieu’s equation [22]. Since, our system isspatially extended, a perturbation may be spatially in-homogeneous. In this case the response of the systemis characterized by
y
n
(
t
) =
y
0
(
t
) +
z
n
(
t
), where
y
0
(
t
) isthe spatially homogeneous and temporally periodic solu-tion described above (see Fig.2), A, and
z
n
(
t
) representsthe perturbations in whose dynamics we are interested.In the most general form the perturbation is given interms of Fourier modes:
z
n
(
t
) =
k
exp[
ikn
]
ξ
k
(
t
) withwavenumber,
k
, and amplitude
ξ
k
(
t
). As with the singleoscillator, the dynamics of the Fourier amplitudes
ξ
k
(
t
)of the perturbation are governed by set of uncoupled ex-tended Hill equations. However, the coefficients of theseequations depend on the wave-number
k
. The Ince sta-bility analysis allows us to analytically determine[23] theFloquet exponents (i.e. the stability criteria) as functionsof the spatial profile as given by
k
. For more technical de-tails on the method see Ref.[24]. The result of our anal-ysis are the stability curves dividing the parameter space(
A/m,
,k
) into stability and instability zones. Figure2, panel B shows the stability boundaries of a spatiallyhomogeneous perturbation (
k
= 0, solid curve) and of astaggered (
k
=
π
, dashed curve) perturbation. Perturba-tions represented by other wave-numbers have stabilityboundaries in-between those shown in Fig.2, B. Belowthese curves the spatially homogeneous states performstable temporal oscillations at the frequency of the exter-
 
3
FIG. 3: The
k
=
π
spatial pattern, at Ω = 2
.
52 THz, ispresented. The upper panel shows evolution of the system.The lower panel shows the power spectrum of the breathermotion.FIG. 4: Breather formation at Ω = 2
.
00 THz. The upperpanel shows the evolution of the breather. The lower panelshows the power spectrum of the breather motion.
nal drive and its higher harmonics, while above the curvethe perturbation leads to period-doubled oscillations. Itis clearly seen that for driving frequencies below Ω
2
.
5THz spatially homogeneous (
k
= 0) perturbations leadto the strongest instability (occurring at the lowest valueof the driving amplitude). However, above Ω
2
.
5 THzthe staggered (
k
=
π
) perturbation becomes the primaryinstability mode. In the region above the stability bound-ary the period-doubled state will therefore tend to adoptthe spatial profile of the most unstable Fourier-mode (ho-mogeneous or staggered). The presence and location of the obtained instability curves (Fig.2,B) were ver-ified by exploring the parameter-space (
A/m,
,k
) bydirect simulations of Eq. (1). The dynamics of smallspatially random (uniformly distributed in the interval[
,
] and thus containing all wave-numbers) perturba-tion
z
n
introduced on top of the spatially homogeneousand temporally periodic solution
y
0
(
t
) was followed nu-merically. As this perturbation injects energy into allwave-numbers, the ensuing dynamics will emphasize themode with the strongest instability. For point A (Fig.2, B), the results are shown in Figure3.The upper panel shows that after the introduction of the pertur-bation (at 40 ps) a spatially staggered structure forms.The power spectrum of this dynamics (lower panel in Fig.3), shows that the frequency of the vibrations is mainly
/
2, i.e. a period-doubling transition has occurred asexpected from the above analysis. The power spectrum(lower panel) shows that the signature of the drive per-sists at Ω, in addition to a component at zero frequency,which results from the asymmetry of the base-pair po-tential
(
y
n
). A similar scenario is observed for drivingfrequencies below Ω
2
.
5 THz, but in these cases thesolutions remain spatially homogeneous after the intro-duction of the perturbation. The fact that the instabilitycurves for 0
< k < π
lie between the two curves in Fig.2,B shows that it is, in general, impossible for any spatiallylocalized feature with a finite (2 base pairs
< λ <
)length scale
λ
to emerge as a result of a linear insta-bility. This is in contrast with many other nonlinearcondensed matter models, where spatially localized andtemporally periodic modes (intrinsic localized modes orbreathers) commonly arise through linear modulationalinstabilities. For our model of dsDNA a perturbationof finite amplitude
is required to create localized un-bindings of the DNA double strand through nonlinearmechanisms. An illustration of this is given in Fig.4for Ω = 2
.
0 THz, where the dynamics caused by a ran-dom perturbation with
>
0
.
14 is shown to result ina localized opening of the DNA double strand. Againthe power spectrum, given in the lower panel of Fig.4shows, as expected, that the localized state vibrates atthe frequency Ω
/
2 in contrast to the uniform background,which remains synchronized to the external drive at Ω.A more detailed study of the nonlinear mechanisms un-derlying the creation of such localized unbinding statesreveals that a localized injection of a certain amount of energy is required. Due to the asymmetry of the basepair potential, an effective way to achieve this is a local-ized
compression 
of the double strand. Using this insightwe found the perturbation
z
n
= 0
.
42cos(
π
4
(
n
n
0
)), for
4
n
n
o
4 (
z
n
= 0 otherwise) to be an effec-tive perturbation for the creation of a localized unbind-ing state at
n
0
, Fig.1.The phase portrait (not shown) of the base pair
n
0
, at the transient time period just beforethe breather is established, reveals the breather forma-tion mechanism. First, the locally injected energy fromthe
compression 
must be sufficient for a few consecutivebase pairs to undergo a temporary local melting transi-tion, i.e. reach the plateau of the Morse potential. Sub-

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