Biophysical Implications of the Peyrard-Bishop-Dauxois model of DNA dynamics

S. Zdravkovi´,1 M. Satari´,2 and J. Tuszy´ski3 c c n
1 Faculty

of Electrical Engineering, University of Pristina, Kosovska Mitrovica, F. R. Yugoslavia

2 Faculty

of Technical Sciences, University of Novi Sad, F. R. Yugoslavia of Physics, University of Alberta, Edmonton, T6G 2J1, Canada (Dated: November 14, 2003)

3 Department

In this paper we expand and elaborate on one of the most widely used nonlinear models of DNA dynamics. A part of this work is dedicated to the parameter of helical interaction within this simple, but not trivial model of a DNA molecule. We also propose an interesting role for the so-called breather solitons emerging from the model and being involved in protein regulation of nonlinear dynamics of DNA. Finally, we examined the possible role of harmonic electric fields in the unzipping of complementary strands of DNA.
Keywords: DNA; PBD model; breather modes; regulatory proteins

I.

INTRODUCTION

Double-helical DNA is a unique polymer. Unlike singly-bonded main-chain polymers, as for example polystyrene, along which the backbone may be appreciably reoriented at a single bond, DNA is very stiff. This is due to the tight constraint of successive pairs of nucleic acids, the so-called base pairs (bp), by chemical and hydrogen bonds [1]. DNA has a thermal bending persistence length of about 150 bp (50 nm). The double-helical structure also exhibits twisting rigidity [2], with a thermal twist persistence length of about 220 bp (75 nm). These elastic properties are stated for “standard” aqueous solutions with 0.14 M univalent salt concentrations. We are exclusively concerned here with the ubiquitous B-double-helix DNA found in vivo. Although there is some variation in the helix repeat distance with base pair sequence, the unstressed B-DNA makes one turn about every 10.5 base pairs or roughly every H = 34 ˚. The spacial angular frequency of an unstressed helix is A
2π H

= 1.85 nm−1 .

2 The diameter of the double helix is about 20 ˚, see Fig. 1. A The persistence lengths for bending and twisting are the natural length scales for thermal fluctuations and, as mentioned above, are 15–20 times H. The comparatively large energetic cost of disrupting the hydrogen bonded structure of base pairs and their helical stacking means that the backbone or central axis of the molecule can be considered inextensible and its distances can be given in either nm or bp. We assume that on the length scales of interest, small irregularities of structures due to specific base pairs are averaged out and we do not consider the effects of strong intrinsic bonds due to phased adenine–thymine (A–T) pairs. The method of fluorescence depolarization is widely used for measurements of the torsional constants of biopolymers. In 1992 Selvin et al. [3] used this method for measurements of the torsional rigidity of relaxed, positively- and negatively-supercoiled DNA. To this end they used time-correlated single-photon counting of an intercalated dye, ethidium bromide. The main result of the measurements was rather unusual, namely the torsional rigidity of the DNA molecule was not constant at all. They found out that at physiological ionic strengths (0.175 M), the torsional rigidity monotonically increases from 1.76 × 10−26 J m for the most positively supercoiled DNA, to 2.28 × 10−26 J m for the most negatively supercoiled DNA. At different ionic strengths the tendencies were similar. From these data the authors drew the conclusion that a DNA molecule is not a linear system. According to realistic estimates, the anharmonic term in the model Hamiltonian for DNA dynamics should account for approximately 15 % of twist fluctuations at room temperature. Moreover many mechanical models dealing with overall DNA dynamics under high tension including overstretching, undertwisting, and supercoiled DNA show without doubt that DNA dynamics have an intrinsically nonlinear character [4]. Therefore, we begin here with persuasive arguments of the nonlinear characteristics of internal DNA dynamics. The possibility that nonlinear effects might focus the vibrational energy of DNA into localized soliton-like objects was first contemplated by Englander et al. [5]. Although several authors [6–12] have suggested that either topological kink solitons or bell-shaped breathers would be good candidates to play a basic role in DNA nonlinear dynamics, there are still several unresolved questions in this regard. A hierarchy of the most important models for nonlinear DNA dynamics was presented by Yakushevich [13]. In the present paper we strongly rely on the extended model for DNA dynamics first proposed by Peyrard and Bishop [8] and later extended by Dauxois [14].

3 The present paper is organized as follows: In Section 2 we first outline the main features of the model discussed which will be henceforth referred to as the PBD model for short. We carefully analyse the necessary conditions for the existence and stability of breather solitons in an idealized homogeneous model considering the role of model parameters, especially the helical spring constant of the DNA chain. We discover that a “window” of favourable values of this parameter exists. The possible role of water molecules regarding this constant is also discussed. The role of water viscosity regarding breather dynamics is also considered. In Section 3 we outline the results of our application of the PBD model to the transmission of regulatory signals along the DNA molecule in the process of regulation of gene expression. We consider the role of regulatory proteins that possess only hydrogen bonds with the DNA. In Section 4 we scrutinise the possible role of endogenous AC fields in the nonlinear dynamics of DNA and try to connect the local fluctuational openings or unzipping of DNA strands predicted by the PBD model to some still unpredictable biological effects in the functioning of living cells. We close this paper with summary and concluding remarks which are reported in Section 5.

II.

THE PBD MODEL

The B-form DNA in the Watson-Crick model is a double helix which consists of two strands labelled s1 and s2 in Fig. 1, linked by nearest-neighbour harmonic interactions along the chains. The strands are coupled to each other through hydrogen bonds, which are supposed to be responsible for transverse displacements of base pairs. Molecular masses of nucleosides (with the attached sugar groups) range from 227 (C) to 267 (G). Thus, the four different base nucleotides (deoxyadenosine, deoxycytidine, deoxyguanosine, and deoxythymidine) differ in mass by less than 18 %, hence the inhomogeneities due to the base sequences are neglected here. Therefore, a common mass parameter m is used for all the bases and the same coupling constant k along each strand is assumed. This is a simplification made in the model and it means that the DNA chain is treated as a perfectly periodic structure. However, it should be noticed that in the discrete PBD model, computer simulations of breather dynamics reveal a very important role of mass inhomogeneities in

4 reflecting or even capturing breathers leading to their growth in fusion processes [15, 16]. The potential energy for the hydrogen bonds connecting A–T or C–G base pairs is modelled by a Morse potential which describes not only the hydrogen bonds but the repulsive interactions of the phosphate groups, partly screened by the surrounding solvent as well. The helicoidal three-dimensional structure of a DNA chain, which is responsible for the stability of the DNA architecture is such that neighbouring base nucleotides from different strands are close enough so that they interact in terms of filaments of solvent. This means that a base at the site n of one strand interacts with both the (n + h) th and (n − h) th bases of the other strand (h = 4), see Fig. 2. Introducing the transverse displacements un , vn of the bases from their equilibrium positions, the Hamiltonian for the DNA chains in the context of the PBD model [14] has the form H=
n

m 2 k (un + vn ) + [(un − un−1 )2 + (vn − vn−1 )2 ] + ˙ ˙2 2 2 + K [(un − vn+h )2 + (un − vn−h )2 ] + D[e−a(un −vn ) − 1]2 2 (1)

where k (respectively K) represents the harmonic constant of longitudinal (respectively helicoidal) springs, see Fig. 2. The Morse potential depicted in Fig. 3 has depth D and its inverse width is a. Criticism of this model could be raised regarding the fact that despite experimentally verified complex motions of DNA chains (even under the action of thermal fluctuations) including stretching, bending and twisting degrees of freedom, the model restricts motions to only two transverse degrees of freedom. We expect that due to long thermal persistence lengths (150–200 bp) at physiological temperatures, conditions prevail that at least within such distances the above restricted model can be justified. The idea is that the complex motion of a DNA chain as a whole can be decoupled into almost independent motions of several degrees of freedom, and the physical expectation is that due to the conspicuous nonlinearity of hydrogen bonds this specific degree of freedom would be favourable for sustaining the expected (and desirable) nonlinear excitations. The latter are good candidates for information transfer along DNA and for local openings of base pairs (fluctuational openings). The elegance of the PBD model is that by using the centre-of-mass coordinates repre-

5 senting the in-phase and out-of-phase transverse motions √ xn = (un + vn )/ 2, √ yn = (un − vn )/ 2 (2)

the corresponding dynamical equations of motion derived from the Hamiltonian in Equation (1) are perfectly decoupled leading to out-of-phase nonlinear equations of motion of the form
√ √ √ m¨n = k(yn+1 + yn−1 − 2yn ) − K(yn+h + yn−h + 2yn ) + 2 2aD(e−a 2yn − 1)e−a 2yn . (3) y

The PBD model was later [17] amended by a different choice of sign for the coordinates involved. On the basis of this choice, the decoupling of in-phase and out-of-phase transverse coordinates is still possible. But, nevertheless the physical picture is thus also inverted. The out-of-phase coordinate obeys a linear dynamical equation of motion while the equation describing the in-phase motion is nonlinear as it includes a Morse potential. This could imply that the breather-like out-of-phase openings are absent within this approach. In our opinion, the breather model is more physically tractable regarding fluctuational openings and unzipping of DNA. According to the original approach of Dauxois [14], it is assumed that the oscillations of bases are large enough to be essentially anharmonic, but still insufficient to break the bonds since the plateau of the Morse potential is not reached. In this respect, the following two-time-scale expansion in the semi-discrete approximation could be relevant yn = εΦn (ε) (ε 1) (4)

Φn (t) = εΨ1 (εn , εt)eiθn + ε2 [Ψ0 (εn , εt) + Ψ2 (εn , εt)ei2θn ] + cc + O(ε3 ) θn = nq − ωt

where = 0.34 nm is the distance between neighbouring base pairs, ω is the optical frequency of the linear approximation of the base pair vibrations and q is the wave number of a carrier wave whose role will be discussed later. Equating the coefficients for corresponding harmonics of the expansion in Equation (4) the main result is that the leading terms obey the nonlinear Schr¨dinger equation below o (subscript τ and S mean derivatives.): iΨ1τ + P Ψ1SS + Q|Ψ1 |2 Ψ1 = 0 (5)

6 where the scaled travelling coordinate S and time τ are S = ε(z − Vg t) and τ = ε2 t, respectively, while the dispersion coefficient P and the coefficient of nonlinearity Q are given by P = 1 ω
2

m

[k cos(q ) − Kh2 cos(qh )] − Vg2 ,

(6a) (6b)

Q = −

2 ωg [2α(µ + δ) + 3β]. 2ω

The remaining parameters (group velocity Vg , ωg , α, µ, β) all arise from the expansions of Equation (4) as follows: Vg =
2 ωg =

ω2 = α = µ =

1 [k sin(q ) − Kh sin(qh )], mω 4a2 D , m 2k 2K 2 ωg − (cos(q ) − 1) + (cos(qh ) + 1), m m −3a √ , 2 −1 4K −2α 1 + , 2 mωg

(7a) (7b) (7c) (7d) (7e) (7f)

7a2 β = . 3

The parameter δ will be defined in this paper in the new form so the physical significance of this step will be discussed shortly. For P Q > 0, Equation (5) has an envelope soliton solution representing a small-amplitude breather for out-of-phase base pair displacement yn of the form (replacing n with z − z0 , where z0 is the position of the centre of a breather) yn = ε2A sech ε (z − z0 − Ve t) × Le ε × cos(Θz − Ωt) + εA sech (z − z0 − Ve t) Le

µ + δ cos[2(Θz − Ωt)] 2

+ O(ε3 ), (8)

where the breather amplitude A, the width Le , the envelope velocity Ve , the carrier wave vector Θ and its frequency Ω are coupled with scaled carrier and envelope velocities (uc , ue )

7 as follows: A = Le = Ve = Θ = Ω = u2 − 2ue uc e , 2P Q 2P , u2 − 2ue uc e Vg + εue , εue q+ , 2P εue ω+ (Vg + εuc ). 2P (9a) (9b) (9c) (9d) (9e)

Our analysis of the conditions of existence and stability for breather solitons in Equation (5) reveals the following important features of the PBD model: Numerical analysis of the necessary condition P Q > 0 for breather existence [18] shows the dispersion coefficient P and the group velocity Vg from Equation (6a) and Equation (7a), depicted respectively in Fig. 4 and Fig. 5. It is readily recognized that the conditions Vg > 0 and P > 0 are satisfied on several intervals of values q . Thus it follows that the wavelength of a carrier wave q =
2π λ

should be an integer multiple of the spacing . This

allowed “window” of carrier wave numbers is a narrow “Brillouin zone” and contains four values λ = (6 , 7 , 8 , 9 ). The breather corresponding to λ = 8 (q = 0.78 rad) is depicted in Fig. 6. It reveals that the breather is represented by a modulated soliton so that the envelope covers approximately twenty oscillations of the carrier wave. A quite new point regarding the PBD model pertains to the parameter β contained in the parameter of nonlinearity Q, Equation (6b). So far this parameter arises from the expansion in Equation (4), connecting the first and second harmonics of this expansion via Ψ2 = δ · Ψ2 . 1 This was done by equating the coefficients for terms exp(i3θn ) or exp(i4θn ) giving constant values for δ. We concluded that a more physically-based approach should be to equate terms for the more influential second harmonic, exp(i2θn ), yielding a new relation between Ψ2 and Ψ1 as follows: 4ω 2 + or δ = 2K 2k 2 2 (cos(2q ) − 1) − (cos(2hq ) + 1) − ωg Ψ2 = ωg αΨ2 1 m m 2k 2K 2 (cos(2hq ) + 1) − ωg 4ω + (cos(2q ) − 1) − m m
2 −1

(10a) (10b)

2 αωg

.

This means that δ is not constant, but rather a function of q . Thus, besides the requirement P Q > 0 that should be satisfied for the breather solution of Equation (5), the adjustable

8 coefficient δ must now satisfy Q > 0 from Equation (6b). In our paper [18] we adopted the set of PBD model parameters from Dauxois [14] and this set reads: k = 3K = 24 N/m, a = 2 × 1010 m−1 , D = 0.1 eV, = 3.4 × 10−10 m, m = 5.4 × 10−25 kg, ue = 105 m/s, uc = 0, ε = 0.007. (11a) (11b) (11c) (11d) (11e) (11f) (11g) (11h)

We should emphasize that the values of these parameters are still controversial. For example, in Dauxois et al. [19] the Morse well was represented as remarkably shallower and narrower (D = 0.04 eV and a = 4.45 × 1010 m−1 ). Nevertheless we relied on Dauxois’ first choice, Equation (11). With the set of parameters in Equation (11) and the nonconstant δ given by Equation (10), the parameter of nonlinearity Q is positive only for a rather large q , see Fig. 7, i.e. for q > 1.36 rad. However, these values for q do not satisfy the other requirements (P > 0, Vg > 0, λ = N , N integer) seen in Fig. 4 and Fig. 5. A possible solution of this controversy is in the assumption that the commonly accepted value of the helicoidal spring constant K = 8 N/m is overestimated. Consequently, we studied the impact of different, smaller values of K. From Fig. 8 we see that Q > 0 holds only for K ≤ 4.6 N/m if q = 0.78 rad (λ = 8 ) is picked. More details about this interesting analysis will be published elsewhere [20], but the general conclusion is that there exists a “window” of values of K leading to the emergence of a breather (0 < K < 4.6) N/m which is the consequence of a straightforward introduction of the parameter δ, in Equation (10). A similar “window” of allowed values of the nonlinearity parameter is known in the theory of Davydov solitons and was the object of controversy about the existence of Davydov solitons at physiological temperatures [21]. A few additional words are in order concerning the helicoidal spring constant K. Recently Peyrard [22] stressed the importance of hydrating water for the biochemical activities of proteins and DNA. Since water molecules are highly polar they form an ordered network

9 on the surface of a protein along which protons can be transferred. The formation of this network with long-range connectivity has been detected as a percolation transition when the water content approaches 0.5 g per gram of protein [23]. We suggest that the helicoidal spring constant in the PBD model may reflect the mediating role of the of the water molecules. Moreover, the helicoidal structure itself arises as the result of optimization of the interplay between hydrogen bonding, hydrophobicity and long-range connectivity. If the helicity is more strongly expressed by the tension of supercoiling, Fig. 9, it should increase the value of K by decreasing the distance of the helicoidally adjacent bases on opposite strands. Increasing the value of K, Fig. 8, would lead to the decrease of Q and thus to an increase in the breather’s amplitudes, see Equation (9a), beyond the Morse plateau causing DNA unzipping. On the other hand, we must take into account the fact that the solvating water does act as a viscous medium that damps out DNA dynamics, favouring energy expenditure. We have also analysed this important biophysical situation in the context of the PBD model [20]. It appears that a viscous force proportional to the velocity of nucleotide oscillations does not impact the out-of-phase base pair dynamics, so we took into consideration a viscous force of the Newtonian kind, proportional to the square of the velocity. The perturbation procedure of “slowly varying coefficients” [24] gives important information about damped dynamics including the slow decrease in the wave’s amplitude and the deceleration of the breather according to a linear function of time: ˜ Ve (t) = Ve0 (1 − Ve0 βt) (12)

˜ Here Ve0 is the initial envelope velocity of the breather and β is a constant dependant on the viscosity and on other parameters of the PBD model.

III.

THE POSSIBLE IMPACT OF REGULATORY PROTEINS ON PBD DYNAMICS

The idea of regulatory signal transmission along DNA came from the results of experiments in which to so-called long-range effects were discovered in DNA [25, 26]. Some regulatory proteins in transcription processes were seen to bind with high efficiency to special segments of a DNA molecule. Numerous experimental data show that even if the distances

10 between attached proteins can reach hundreds or thousands of base pairs, they exhibit mutual influence [27]. To explain this effect many alternative models of the action at a long distance have been proposed. Our preferred assumption is that binding one regulatory protein molecule to DNA produces an excited state which is accompanied by a local conformational distortion of a base pair generating a breather excitation or enhancing the amplitude and the speed of an already existing decelerated breather. Such a breather propagates along the DNA chain and upon reaching the target site changes the conformational state of the site, which in turn, changes the binding constants for a second protein. This enables it to be attached via the lock-and-key mechanism to the same DNA chain. Specific interactions of regulatory proteins with DNA are usually defined through hydrogen bond interactions between functional groups of amino acid side chains or peptide bonds and groups of base pairs in the major or minor grooves of the DNA chain. We here restrict our consideration to those regulatory proteins that possess only hydrogen bonds with the DNA. Fig. 10 represents the amino acid glutamine bound by two hydrogen bridges to a A–T base pair in the minor groove. We here recall that every protein has a peptide group which contains a double-bonded carbon-oxygen complex (or amide-I bond) with a characteristic quantum of energy of 0.205 eV (corresponding to a spectral peak at 1650 cm−1 ). The amide-I bond appears to be of great interest here as a potential “basket” for storage and transport of biological energy. This part of an glutamine molecule is indicated in Fig. 10 by a circle. The amide-I exciton mode was given a prominent place in the theory of Davydov molecular solitons that was also applied to α-helical chains [20]. However, a problem arises when we realize that at a single peptide group, the lifetime of an amide-I vibration is of the order of 10−12 s [20]. We conjecture that the energy of this mode which is comparable to the depth of the Morse potential well of neighbouring base pairs (D = 0.2 eV) could be utilized in producing a conformational change of the respective A–T base pair. This energy transfer is supposed to be mediated by hydrogen bonds of an glutamine attachment to DNA depicted by a rectangle in Fig. 10. Finally, the hydrogen bonds within a A–T base pair are in the ellipsoidal area. In order to describe the possible mechanisms of long-range signal propagation induced by regulatory proteins, we start from the nonequilibrium statistical approach presented by Zubarev [28], and straightforwardly performed in our recent paper [29]. Here, we only outline the main features and results of this method.

11 Let us first introduce the extended Hamiltonian in an attempt to model the above regulatory process in DNA. The Hamiltonian should consist of two parts as follows: H = H0 + Hint , (13)

where the Hamiltonian H0 consists of two terms, the first of which represents the part of the PBD Hamiltonian Equation (1) containing the separated coordinates yn and momenta Pyn = myn , while the second one corresponds to the amide-I mode in the regulatory protein, ˙ considered here. Hence, H0 = Hy + HC=0 ,
2 Pyn 2m

(14)

Hy =

n

+ k (yn − yn−1 )2 + 2
√ 2ayn

K [(yn 2

− yn−4 )2 (15)

+(yn − yn+4 )2 ] + D(e− and
+ HC=0 = Eκ Cκ Cκ ,

− 1)2 ,

Eκ = hΩκ = 0.205 eV, ¯

(16)

+ where Eκ is the energy of the amide-I mode, while Cκ , Cκ represent the creation and

annihilation operators, respectively, of an excited state possessing the wave vector κ. Finally, Hint describes the interaction between the amide-I mode and the nearest base paris of DNA. It could be conveniently written in the form Hint =
n op Hint fn (t)

(17)

where the operator part of the interaction is given as follows
op + Hint = (Cκ + Cκ )yn

(18)

while the Heaviside-type interaction switching function has the form fn (t) = F0 e−σ
2 (m−

)2

{θ(t − τ (n − 1)) − θ(t − τ (n + 1))}. ˜ ˜

(19)

Since we already used τ for a variable in Equation (5) we now use a modified symbol τ in order to avoid confusion. We assumed here that due to its hydrogen character, the ˜ interaction term drops exponentially with distance from its original magnitude F0 . It is also

12 assumed here that the protein molecule is located at site of the DNA chain. The Fourier

transform of the time-dependent part of the interation in Equation (19) 1 fn (t) = 2¯ u yields fn (ω) = 2F0 e−σ
2 (n−

+∞

dω e−iωt fn (ω)
−∞

(20)

)2

sin(˜ω) iω˜n τ e τ . ω

(21)

Since the breather-solitons in DNA can be generated in different ways, various causes that have been suggested include the thermal fluctuations as well as local ligand-protein interactions considered here, in addition to the chemical energy released during ATP hydrolysis. It is apparent to us that in a very long DNA chain an ideal gas of breathers can be generated via one or several of these mechanisms. Consequently, we need to develop a statistical approach in order to compute the average value of the base pair displacement resulting in the process. For this purpose we use the well-known method of nonequilibrium statistical mechanics developed by Zubarev [28] according to which the average value of an ˆ arbitrary physical operator A can be evaluated as

A = A
t2

0+ m=1

1 i¯ h
tn−1

m

t

t1

dt1
−∞ −∞

dt2 (22)

×
−∞

dt3 · · ·
−∞

dtn−1 Tr{A(t)[Hint (t1 )

× [Hint (t2 ) · · · [Hint (tn ), ρ0 ]]}, where A
0

is the average value with respect to the density matrix ρ0 pertaining to the

system (Equation (15) and Equation (16) unperturbed by the interaction, Equation (17). The square brackets above stand for the corresponding commutators, and Tr means the trace. If we retain only the two leading terms, Equation (22) then yields 1 A = A 0+ i¯ h − 1 h2 ¯
t dt1 t

dt1 Tr{A(t)[Hint (t1 ), ρ0 ]}
−∞

dt1
−∞ −∞

dt2 Tr{A(t)[Hint (t1 ), [Hint (t2 ), ρ0 ]]}

(23)

13 Substituting A = yn , into Equation (23) gives for the average displacement at lattice site n:
+∞ +∞ op dt1 yn (t)|Hint (t1 ) f (t1 ) + −∞ −∞

yn = yn
+∞

0+

d˜1 τ (24)

×
−∞

op op d˜2 yn (0)|Hint (−˜1 ) Hint (−˜1 − τ2 ) τ τ τ ˜

× f (t − τ1 )f (t − τ1 − τ2 ) · · · , ˜ ˜ ˜ where the Green’s functions have been introduced as follows: yn (0)|Hint (−˜1 ) Hint (−˜1 − τ2 ) τ τ ˜ 1 θ(˜1 )θ(˜2 )Tr{yn (0) τ τ = (i¯ )2 h ×[Hint (−˜1 ), [Hint (−˜1 − τ2 ), ρ0 ]]} · · · . τ τ ˜

(25)

Calculating the average out-of-phase base pair displacements along the DNA chain, after tedious algebraic steps one obtains [29]: yn = yn where · · ·
0 0

1+

2 √ 8F0 D˜2 τ 2 τ 2 2 sin (˜Ωκ ) 2 exp(−2 2ayn ) m¯ Ωκ h

0

√ − exp(− 2ayn )

(26)
0

stands for the corresponding averages along DNA in the absence of the amide-I

trigger mode; the parameters a, D and m are listed in Equation (11), F0 stands for the magnitude of the force attributed to the hydrogen bonding amide-I mode–base pair (G–C) interaction, and τ is supposed to be equal to the amide-I mode lifetime (˜ = 10−12 s). The ˜ τ most recent estimates of the hydrogen bonding force reveal that F0 8 pN.

From Equation (26) it follows that for resonantly coupled energy and lifetime in the “quantized” form π τ Ωκ = (2k + 1) ; ˜ 2 k = 0, 1, 2, . . . (27)

the amide-I triggering would contribute maximally to the process considered. The average yn can be estimated taking yn
0

= 10−11 m, see Dauxois et al. [19]. The estimate reveals

that due to the presence of glutamine the average “breathing” of the out-of-phase mode could reach as much as yn = 0.5 ˚ which is on the order of the fluctuational openings of A DNA. It could therefore be inferred that the regulatory proteins may remarkably support the increase of the average amplitude of breather excitations in DNA enabling them to sustain over longer distances and to reach target sites in order to switch them on or off, as required by biological processes.

14
IV. ENDOGENOUS AC FIELDS AND PBD DYNAMICS

We have recently investigated thoroughly the possible role of electromagnetic fields in DNA dynamics in the context of the PBD model [30] discussed in the present paper. Our interest in this topic was piqued by the experimental evidence [31] that in yeast cells signals within the range (50–70) MHz were detectable. These fields could perhaps be attributed to coherent oscillations of dipolar membranes of the cells or their nuclei. On the other hand, it was reported that switching electric fields may exist within and around microtubules due to their ferroelectric properties. The amplitude of such fields in microtubules was estimated [32] to be on the order of E0 = 2.6 × 106 V/m. We analysed statistically, using the Kubo linear response method [30], the possible resonant effect of the harmonic electric field E = E0 sin(ω0 t) (28)

with magnitude E0 and frequency ω0 transversally polarized with respect to the linear DNA chain. The corresponding Hamiltonian representing the interaction of an “ideal gas” of breathers with the applied AC field can be introduced starting from the leading term of Equation (8), (with z = 0 and t = 0) and from Equation (16), as follows
Nb

W (t) = qeff E0 sin(ω0 t)
j=1

2εA

cos(Θz0j ) cosh
ε z Le 0j

(29)

where qeff is the effective protonic charge in the displaced base pair, and the summation with respect to j represents the initial distribution of centres of Nb breathers along the DNA chain. In order to estimate the average stretching of base pairs involved when breathers are driven by an external electric field, we introduced the average transveral displacement yn as follows: yn = yn Here the equilibrium average yn equilibrium canonical ensemble as
+∞ N 0 0

+ ∆ yn

field

.

(30)

at temperature T is calculated with respect to the

yn

0

= (Zh )

N −1 −∞ n=1

dPyn dyn yn e−βHy ;

β = (kB T )−1

(31)

15 where Z stands for the corresponding partition function, h is Planck’s constant, Pyn = myn , ˙ and Hy is the Hamiltonian given by Equation (15). For physiological conditions we estimated [30] that yn
0

1 × 10−11 m,

(32)

which is highly in accordance with Dauxois et al. [19]. This is significantly beyond average thermal fluctations, which are on the order of 0.2 × 10−11 m but still insufficient for local unzipping of a DNA chain. The linear response term of Equation (30) has the form

∆ yn where the time derivative and Equation (15);
∂yn ∂t

field


0

dt

∂yn W (t) ∂t

,
0

(33)

follows from the classical Poisson bracket for a Hamiltonian

∂yn ∂Hy = {yn , Hy } = . ∂t ∂Pyn Replacing W (t) and
∂yn ∂t

(34)

in Equation (33) one gets B ∞ −βm∗ Ve2 ∆ yn field = dVe m∗ exp (εA)2 h 0 2 +∞ ∞ 1 dz0 cos(Θz0 ) dt[cos(ω0 t)] × −∞ cosh((ε/Le )z0 ) 0 +∞ sin(Θz − Ωt) . × dz cosh[(ε/Le )(z − z0 − Ve t)] −∞

(35)

where B = 4E0 qeff βΩ exp(−βE0 ), m∗ = 4 m 15 A2 ε 2 Le , (36)

Ve is the envelope velocity, see Equation (9c), and E0 is the bound energy of a single breather, E0 0.1 eV. After making the appropriate calculations of Equation (35) and by using the set of parameters proposed by Dauxois, see Equation (11), but instead using the new value K = 4 N/m,

16 we estimated qeff = 2 × 10−19 C, A = 3 × 10−8 m, Le = 1 × 10−11 m, Ω = 0.5 × 1012 s−1 , Θ = 1.5 × 109 m−1 , q = 2.3 × 109 m−1 , Ve = 1.6 × 103 m/J, m∗ = 3 × 10−26 kg, (37a) (37b) (37c) (37d) (37e) (37f) (37g) (37h)

which enables us to get the field induced nonequilibrium displacement in the following form ∆ yn
field

= 2 × 10−15 (E0 ω0 ) ˚. A

(38)

Thus, under extremely favourable conditions, a strong local electric fields with a magnitude on the order of 106 V/m [32], and with a frequency of 7 × 107 Hz [31], gives on the basis of Equation (38) very significant average displacements of ∆ yn
field

0.9 ˚. A

(39)

This number is close to the threshold of local unzipping which is about 1 ˚. It could be thus A concluded that extremely high intrinsic endogenous AC fields could have effects on DNA quite similar to those of high energy photons [33]. In this context the possible influences on living cells of “electromagnetic smog” produced by massive use of ever increasing frequencies should be considered seriously. Cellular telephones with working frequencies of roughly 2 GHz are particularly interesting in this respect.

V.

CONCLUSIONS AND DISCUSSION

In this paper we have revisited the Peyrard-Bishop-Dauxois model of DNA dynamics and showed some of our applications of this interesting model to important biological consequences of nonlinear DNA dynamics.

17 In Section II we briefly outlined the physical establishment of the PBD model and a corresponding algorithm leading to a nonlinear Schr¨dinger equation and its breather mode o solution. We introduced a new choice of the parameter δ, see Equation (10), which is incorporated in the coefficient of nonlinearity Q, see Equation (6b). By numerical analysis we have shown that with this choice of δ the value of the helicoidal spring constant K must be revised. We found the the “window” of possible values is such that 0 N/m < K < 4.6 N/m. The role of hydrating water in sustaining the interaction which is responsible for the helicoidal spring was stressed by Peyrard [22]. We took the next step, considering the viscosity of the hydrating water and its impact on the breather’s dynamics. The perturbation technique used shows that breathers persist with stable but linearly decelerated motion. In Section III we examined a very interesting biological application of PBD breathers the mediators for regulatory proteins’ interactions with DNA. We analysed the specific example of the amino acid glutamine attached by hydrogen bonds to an A–T base pair in the major groove of a B-DNA helix. Our basic assumption is that amide-I bond excitation plays the role of a trigger for high amplitude breather formation. Section IV starts from the breather function, Equation (8), and examines the interaction of an “ideal gas” of breathers with a harmonic AC field. Kubo formalism leads to the expression in Equation (38) which indicates the possible role of strong fields with high frequencies in unzipping of DNA chains with profound physiological consequences. Finally, we give a few general remarks regarding the PBD model. It is clear that this simple version for an ideal homogeneous DNA chain does not pertain to real circumstances where inhomogeneities either with respect to mass or to hydrogen bond number (two or three) could play an important role in DNA dynamics. Nevertheless, on the basis of exhaustive numerical results [34–36] it was concluded that this additional interplay between nonlinearity, discreteness, and inherent inhomogeneity within the PBD model sustains the stability and higher localization of breather excitations, making them candidates for diverse DNA functions. Recently, substantial progress was made in experiments where single DNA strands within a genome are manipulated and the forces necessary for separation of complementary strands are measured [37]. Establishing the connections between the parameters of theoretical models, such as the PBD model, and experimental results is the next stage in this particularly

18 important field of biophysics.

Acknowledgments

The authors thank Prof. John Marko of the University of Illinois, Chicago for very stimulating discussions during his visit to Edmonton. We are also grateful to Prof. Michel ´ Peyrard of the Ecole Normale Sup´rieure de Lyon for inspiration. This project has been e supported by funds from NSERC, MITACS-MMPD and the Theoretical Physics Institute at the University of Alberta.

[1] J. Darnell, H. Lodish and D. Baltimore, Molecular Cell Biology, Scientific American Books, New York (1990), pp. 68–72 [2] J. F. Marko and E. D. Siggia, Phys. Rev. E 52 (1995) 2912–2938 [3] P. R. Selvin, D. N. Cook, N. G. Pon, N. R. Bauer, M. P. Klein and J. E. Hearst, Science 255 (1992) 82–85 [4] J. F. Marko, Phys. Rev. E 57 (1998) 2134–2149 [5] S. W. Englander, N. R. Kalenbach, A. J. Heeger, J. A. Krumhansl and S. Litwin, Proc. Natl. Acad. Sci. USA 77 (1980) 7222–7226 [6] S. Homa and S. Takeno, Prog. Theor. Phys. 72 (1984) 679–693 [7] V. Muto, A. C. Scott and P. L. Christiansen, Phys. Lett. A 136 (1989) 33–36 [8] M. Peyrard and A. R. Bishop, Phys. Rev. Lett. 62 (1989) 2755–2758 [9] M. Salerno, Phys. Rev. A 44 (1991) 5292–5297 [10] S. N. Volkov, J. Theor. Biol. 143 (1990) 485–496 [11] S. Yamosa, Phys. Rev. A 30 (1984) 474–480 [12] G. F. Zhou and C. T. Zhang, Phys. Scripta 43 (1991) 347–352 [13] L. V. Yakushevich, Nonlinear Physics of DNA, Wiley series in Nonlinear Science, John Wiley, Chichester (1980) [14] T. Dauxois, Phys. Lett. A 159 (1991) 390–395 [15] T. Dauxois and M. Peyrard, Phys. Rev. Lett. 70 (1993) 3935–3938 [16] K. Forinash, M. Peyrard and B. Malomed, Phys. Rev. E 49 (1994) 3400–3411

19
[17] G. Gaeta, Phys. Lett. A 172 (1993) 365–372 [18] S. Zdravkovi´ and M. V. Satari´, Phys. Scripta 64 (2001) 612–619 c c [19] T. Dauxois, M. Peyrard and A. R. Bishop, Phys. Rev. E 47 (1993) 684–695 [20] S. Zdravkovi´, M. V. Satari´ and J. A. Tuszy´ski, Extended Peyrard-Bishop model and DNA c c n dynamics (????), submitted [21] A. C. Scott, Phys. Rev. A 26 (1982) 578–595 [22] M. Peyrard, J. Biol. Phys. 27 (2001) 217–228 [23] G. Carreri, M. Geraci, A. Giansanti and J. A. Ruply, Proc. Natl. Acad. Sci. USA 82 (1985) 5342–5346 [24] N. N. Bogoliubov and Y. A. Mitropolskii, The Asymptotic Method in the Theory of NonLinear Vibrations, Nauka, Moscow (1974), (in Russian) [25] D. M. Crothers and M. Fried, in Cold Spring Harbour Symposia on Quantitative Biology, vol. 47 (1983) [26] M. Ptashene, Nature 332 (1986) 697–701 [27] R. R. Sinden, DNA Structure and Function, chap. 8, Academic Press (1994) [28] D. N. Zubarev, Nonequilibrium Statistical Thermodynamics, Consultants Bureau (1974) [29] M. V. Satari´ and J. A. Tuszy´ski, Phys. Rev. E 65 (2002) 051 901,1–10 c n [30] M. V. Satari´, Physica D 126 (1999) 60–68 c [31] R. H¨lcel and I. Lamprecht, Neural Net. World 4 (1994) 327–337 o [32] B. Trpi¯ova and J. A. Tuszy´ski, Phys. Rev. E 55 (1997) 3288–3305 s n [33] J. J. Ladik, Journ. of Molec. Structure 277 (1992) 109–115 [34] T. Dauxois and M. Peyrard, Phys. Rev. E 51 (1995) 4027–4040 [35] K. Forinash, T. Cretegny and M. Peyrard, Phys. Rev. E 55 (1997) 4740–4756 [36] M. Peyrard, Physica D 119 (1998) 184–199 [37] B. Essevaz-Roulet, U. Bockelmann and F. Heslot, Proc. Natl. Acad. Sci. USA 94 (1997) 11 935–11 940

20

FIG. 1: The Watson-Crick double helix model of the DNA molecule with characteristic dimensions. Figures

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transverse displacements of each base pair. FIG. 2: Illustration of the PDB model including elastic constants introduced and the assumed

21

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FIG. 3: Representation of the Morse potential with depth D and inverse length a.

40 P (10−7 m2 /s) 20 0 -20 0 1 2 3 4 q (rad) 5 6

FIG. 4: Dispersion coefficient P of the NSE versus q for Equation (6a). 

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see Equation (7a).

2 Φ (nm) 1 0 -1 -2 48 50 52 54 56 t (ps) 58 60 62

FIG. 6: The breather corresponding to the chosen λ = 8 (q = 0.78 rad).

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0 -10 -20 -30 -40 0.0 0.5 1.0 q (rad) 1.5 2.0

FIG. 7: Nonlinear coefficient Q of the NSE as a function of q (K = 8 N/m), from Equation (6b).

24
100 50 0 0 1 2 3 4 K (N/m) 5 6 7

FIG. 8: Nonlinear coefficient Q of the NSE as a function of K (q = 0.78 rad), from Equation (6b) and Equation (10).

Q (1032 m−2 s−1 )

FIG. 9: Supercoiling of DNA.

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25

FIG. 10: The amino acid glutamine bound as if in the major grove by two hydrogen bonds (rectangle) to a adenosine–thymine base pair. The amide-I bond is circled; note the hydrogens bonding between the two bases are in the elipse.

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