The effect of applied external electric field on DNA occurs mostly at high field intensity. The results of a theoretical ab initio study of effects of applied electric field on G:C base pair components are reported. The geometries of the local minima were optimized without the symmetry restrictions by the gradient procedure at density-functional level of the theory and were verified by calculations of the second derivative of energy. The standard CEP-31G basis set was used. The geometrical parameters, relative stability and interaction energies are reported. The electric field mutation could be classified as a multi-point mutation.Učinak vanjskog električnog polja na DNA javlja se najčešće za jaka polja. Izvješćujemo o ishodima proučavanja učinaka vanjskog električnog polja na sastavnice baznog para G:C polazeći od osnova teorije. Razmještaj lokalnih minimuma smo optimizirali bez ograničenja na uvjete simetrije rabeći gradijentan postupak na razini teorije funkcionala gustoće i provjerili računima drugih derivacija energije. Primijenili smo uobičajen osnovni skup CEP-31G. Izvješćujemo o promjenama razmaka, stabilnosti i energijama međudjelovanja. Mutacije električnim poljem mogle bi se razvrstati u višemjesne mutacije

Abdalla, Zainab S.

Al-anber, Mohanned J.

Salih, Afrodet A.

English

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Printed ISSN 1330–0008Online ISSN 1333–9125CD ISSN 1333–8390CODEN FIZAE4THEORETICAL AB INITIO STUDY OF THE ELECTRIC FIELD EFFECTSON THE STRUCTURE AND STABILITY OF G:C BASE PAIRMOHANNED J. AL-ANBERa, ZAINAB S. ABDALLAb and AFRODET A. SALIHbaPhysical Department, College of Science, Basrah University, Basrah, IraqbChemical Department, College of Science, Basrah University, Basrah, IraqReceived 27 May 2008; Accepted 17 December 2008Online 12 February 2009The effect of applied external electric field on DNA occurs mostly at high fieldintensity. The results of a theoretical ab initio study of effects of applied electricfield on G:C base pair components are reported. The geometries of the local min-ima were optimized without the symmetry restrictions by the gradient procedureat density-functional level of the theory and were verified by calculations of thesecond derivative of energy. The standard CEP-31G basis set was used. The geo-metrical parameters, relative stability and interaction energies are reported. Theelectric field mutation could be classified as a multi-point mutation.PACS numbers: 87.15.-v, 87.15.Aa UDC 539.199, 539.194Keywords: DFT, DNA, ab initio calculation, electric field effect, mutating1. IntroductionAfter accurately describing the structure of DNA, Watson and Crick suggestedthe effects of spontaneous mutations on DNA [1]. DNA can be damaged by manydifferent sorts of mutagens. These include oxidizing agents, alkylating agents andalso high-energy electromagnetic radiation such as ultraviolet light and X-rays. Thetype of DNA damage produced depends on the type of mutagen. For example, UVlight mostly damages DNA by producing thymine dimers, which are cross-linksbetween adjacent pyrimidine bases in a DNA strand [2]. On the other hand, oxi-dants such as free radicals or hydrogen peroxide produce multiple forms of damage,including base modifications, particularly of guanosine, as well as double-strandbreaks [3]. It has been estimated that in each human cell, about 500 bases sufferoxidation damage per day [4,5]. The most serious damage of these oxidative le-sions are the double-strand breaks, as these lesions are difficult to repair and canFIZIKA A (Zagreb) 17 (2008) 4, 151–158 151al-anber et al.: Theoretical ab initio study of the electric field . . .produce point mutations, insertions and deletions from the DNA sequence, as wellas chromosomal translocations [6]. Chemically induced or exogenous methylationoccurs as a result of exposure to chemical agents such as nitrosamines, di-methylsulfate, and 1,3-bis(2-chloroethyl)-1-nitrosourea. Recently, attention has been givento the nitrosamines, which are a principle alkaloids found in tobacco smoke (theymake methylation base pairs) [7]. However, partly due to its influence on hydrogenbonding, methylation is the most pro-mutagenic methyl adduct formed and canboth silence gene expression and cause point mutations [8]. Epigenetic methylationoccurs at the guanine and cytosine of CpG islands in DNA and is regulated byan organism’s methyltransferases and other enzymes. These enzymes interact withDNA by flipping the target base out of the double helix and into its active site [9].The term base flipping is commonly used to describe the rotation of single baseout of the double helix as a result of attractive and repulsive forces imparted byenzyme’s active site constituents.The aim of this theoretical investigation is to use ab initio approaches [10] tocharacterize the nature of changes in the interaction energy and molecular structurein G:C base pairs under the applied external electric field. To accomplish this,we analyzed the changes in the molecular geometry and the interaction energycomponents [11].2. Theoretical approach and computational detailsTheoretical calculations are used to bridge gaps in the understanding of exper-imental results. In many cases the results of the experimental methods are unableto accurately describe small components of a complex biochemical. The methodsof molecular quantum mechanics can be used to investigate properties beyond thescope of current crystallographic methods. The molecular quantum techniques allowus to study optical, magnetic and electronic properties which are not easily mea-sured experimentally. The molecular quantum mechanics provides the interactionenergies that are not provided by the X-ray and NMR experiments. The theoreticalmethods can be used to further investigate and predict the physical and chemicalnature of hydrogen bonding interactions. The predictive power of computationalbiology for DNA has been confirmed in the recent experimental investigation whichconcluded that amino groups in cytosine and adenine are non-planar [12]. This waspostulated and predicted by the molecular quantum calculations over 10 years ago[13]. Ab initio calculations were performed to study the G:C base pair using theGaussian 98 program [14]. The geometries for normal (field-off) and electric field-on G:C base pairs were fully optimized at density-functional-theory (DFT) levelwith the CEP-31G basis set using the gradient optimization method. The appliedDFT method used the B3LYP hybrid functional (a parameterized combination ofBecke’s exchange functional, the Lee, Yang and Parr correlation functional and theexact exchange) [15].152 FIZIKA A (Zagreb) 17 (2008) 4, 151–158al-anber et al.: Theoretical ab initio study of the electric field . . .3. Stability of cytosine, guanine and G:C base pairsThe change in optimized total energies (∆Et = Enormal − Efield), as a functionof applied electric field, of guanine, cytosine and G:C base pairs considered in thisstudy are collected in Tables 1, 2 and 3, respectively. Calculations for the guanineand cytosine alone (in gas phase) gave changes in stability of these molecules. Theapplied electric field in the x direction decreases the guanine stability, while itsstability increases for other directions. The applied electric field in the z direction,which is perpendicular to the plane of guanine molecule, shows low effect comparedwith the y direction. In the case of cytosine base the applied electric field in the xand y directions decrease the stability, while the z direction field show low increasesin the cytosine stability. For a weak applied electric field in the x direction, thestability of the G:C base pair decreases, but as the field increases, the stabilityincreases. The applied electric fields in the y and z directions produces a decreaseof G:C base pair stability. These two directions showed approximately the sameeffect. The enzyme of helicase, which is unwinding DNA, is corresponding hard inthe operation of separating the double helix of DNA.TABLE 1. The total energies (in Kcal/mol) of guanine at different levels of theelectric field in the x, y and z direction, estimated at the B3LYP/CEP-31G level.Electric field (a.u.) x-direction y-direction z-direction0.0001 –0.10089 0.156969 0.0002050.0010 –1.05025 1.600899 0.0081050.0100 –5.24153 19.22036 0.060635TABLE 2. The total energies (in Kcal/mol) of cytosine at different levels of theelectric field in the x, y and z direction, estimated at the B3LYP/CEP-31G level.Electric field (a.u.) x-direction y-direction z-direction0.0001 –0.12064 –0.14021 8.58E-050.0010 –1.18499 –1.43871 0.008790.0100 –13.762 –2.73721 0.919663TABLE 3. The total energies (in Kcal/mol) of G:C base pairs at different levelsof the electric field in the x, y and z direction, estimated at the B3LYP/CEP-31Glevel.Electric field (a.u.) x-direction y-direction z-direction0.0001 –0.16795 –0.0269 –0.003340.0010 1.788492 –0.20783 –0.289020.0100 27.27538 –0.38876 –20.1515FIZIKA A (Zagreb) 17 (2008) 4, 151–158 153al-anber et al.: Theoretical ab initio study of the electric field . . .4. Hydrogen bonding energy of G:C base pairsThe less computationally expensive B3LYP/CEP-31G method describes hy-drogen bonding interactions in G:C base pairing in good agreement with higher-level MP2 calculations [16]. Normal of G:C base pairs considered in this studyare shown in Fig. 1. The hydrogen bonding (HB) energy of normal G:C base pair,EHB = EG:C− [ECytosine+EGuanine], without electric field, is equal to –34.05268053Kcal/mol. The hydrogen bonding energies between the G:C base pair as a func-tion of the electric field, are shown in Table 4. It should be noted that, for theapplied electric field in the x direction of G:C base pair coincident with axes ofhydrogen bonding complexes, they differ significantly from the other two directionsFig. 1. The optimized normal G:C base pair at the B3LYP/CEP-31G level.TABLE 4. The hydrogen bonding energies (in Kcal/mol) of G:C base pairs atdifferent levels of the electric field in the x, y and z direction, estimated at theB3LYP/CEP-31G level.Electric field (a.u.) x-direction y-direction z-direction0.0001 –34.1063 –34.009 –34.04910.0010 –38.0764 –33.6827 –33.74680.0100 –80.3316 –30.6528 –12.9209with respect to intermolecular bond distances. In the former case, the hydrogenbonding energy increases, while in other two directions, the hydrogen bondingenergy decreases. The applied electric field in the z direction, coincident with thenormal direction to the plane of the G:C base pair, does not show large effect in154 FIZIKA A (Zagreb) 17 (2008) 4, 151–158al-anber et al.: Theoretical ab initio study of the electric field . . .this direction. The applied electric field in the direction of the hydrogen bond mayinterfere in the enzyme role in the separation of the DNA sheets, which may lead toerrors in the processes of DNA copying. In general, we hypothesize that the genesin the electric field may be silenced, because of the inability of bases to flip outof the double helix into the active site of enzymes due to the stronger hydrogenbinding interactions. In an aberrant G:C base pair in an electric field at an O17atom, the electric field acts on the hydrogen bond causing it to lose its ability toparticipate in one of its three hydrogen bonds, leaving it susceptible to mis-pairingwith bases, which is typical for two hydrogen bonds in thymine. This case may besimilar to the methylation effect [16].5. Geometry analysis of G:C base pairsThe changes in the optimized hydrogen bond distances as a function of ap-plied electric field, ∆rHB, are collected in Table 5. The calculations were madefor a normal G:C base pair in order to note the electric field effect on the hy-drogen bond distances. The calculations of the effect of the electric field (equalto 0.0001 au) in x, y and z directions produce hydrogen bond distances thatclosely resemble those of normal G: C base pair. For the electric field equal to0.001 au in x and y directions, the most pro-mutagenic of all fields, differencesfrom normal G:C pairing are found in two ways. First, the change of the hy-drogen bond distance between guanine (H25) and cytosine (N6) atoms is 0.164Å. Second, there is a 0.321 Å extension of the hydrogen bond distance betweenguanine (O8) and cytosine (H29) atoms, more than in the above case. Thisindicates an opening of the hydrogen bond at the down site of the pair andTABLE 5. The change in the hydrogen bond distances (Å) of G:C base pair underelectric field at the B3LYP/CEP-31G level.Electric field (a.u.) ∆r(O17 − H13) ∆r(H25 − N6) ∆r(H29 − O8)Ex(0.0001) 0.001 0.001 0Ex(0.001) 0.03 0.164 0.321Ex(0.01) –0.227 –0.041 0.24Ey(0.0001) 0.001 0 0Ey(0.001) 0.03 0.164 0.321Ey(0.01) 0.016 –0.0058 –0.0079Ez(0.0001) –0.003 0.001 0Ez(0.001) –0.0117 –0.0156 –0.0176Ez(0.01) –0.227 –0.041 0.24FIZIKA A (Zagreb) 17 (2008) 4, 151–158 155al-anber et al.: Theoretical ab initio study of the electric field . . .the middle site. The electric field effects on the G:C base pair differs from theeffect of tobacco smoke, which is doing methylation in the G:C base pair, accordingto results of G. Forde et al. [16]. Due to the changes in the properties of regionsof DAN by methylation, the third hydrogen bonding between the G:C base pairdecreases, while with the electric field it does not change. From the geometricaldata, it should be noted that the geometrical factors due to all electric field effectsdiffer significantly with respect to the intermolecular bond distances. The effectof the electric field on the hydrogen bond distances is large when the externalelectric field is applied in the directions coincident with the plane of G:C basepair. Moreover, the applied strong electric field, in the direction that is coincidentwith the plane of G:C base pair, is significant enough to disrupt two of the threehydrogen bonds in the G:C base pair.6. ConclusionIn summary, the results of our calculations show that the applied electric fieldon G:C base pairs causes significant changes in the interaction between guanine andcytosine compared to the Watson-Crick hydrogen-bonding pattern. This probablyis a result of inductive and steric effects. As a result, the changes in G:C hydrogenbonding energies may increase the energy required for base flipping and it mayexceed that what is provided by the enzyme responsible for this process. Our resultsare summed up by the following:• Based on our data, the effects of high electric field may introduce significantchanges in the geometrical parameters of base pairs. In the case ∆rH29−O8 = 0.321Å, which is known to cause base transitions, it is shown that one of the hydrogenbonds is lost. As a result, DNA polymerase under the high electric field couldincorporate a thymine into the daughter strand produced from a guanine.• We have found that changes in the interaction energies in G:C base pairs (withapplied electric field) do directly correlate to adduct pro-mutagenicity.• Our data reveal that electrostatic contributions predominate in interactionsof all investigated complexes.• The order of stability of guanine, cytosine and G:C base pair is a function ofelectric field intensity and direction.• The applied high electric field on G:C base pair increases intermolecular bond-ing energies.• Finally, the electric field may be able to produce the multi-point mutations.References[1] J. Watson and F. Crick, Nature 171 (1953) 737.[2] T. Douki, A. Reynaud-Angelin, J. Cadet and E. Sage, Biochemistry 42 (2003) 9221.[3] J. Cadet, T. Delatour, T. Douki, D. Gasparutto, J. Pouget, J. Ravanat and S. Sauvaigo,Mutat. Res. 424 (1999) 9.156 FIZIKA A (Zagreb) 17 (2008) 4, 151–158al-anber et al.: Theoretical ab initio study of the electric field . . .[4] M. Shigenaga, C. Gimeno and B. Ames, Proc. Natl. Acad. Sci. USA 86 (1989) 9697.[5] R. Cathcart, E. Schwiers, R. Saul and B. Ames, Proc Natl. Acad. Sci. USA 81 (1984)5633.[6] K. Valerie and L. Povirk, Oncogene 22 (2003) 5792.[7] S. Hecht, Chem. Res. Toxicol. 11 (1998) 560.[8] B. Singer and D. Grunberger, Molecular Biology of Mutagens and Carcinogens, PlenumPress, New York (1983).[9] R. Roberts, Cell 82 (1995) 9.[10] J. Sponer, J. Leszczynski and P. Hobza, J. Phys. Chem. 100 (1996) 1965.[11] W. Sokalski, S. Roszak and K. Pecul, Chem. Phys. Lett. 153 (1988) 153.[12] F. Dong and R. Miller Science 298 (2002) 1227.[13] J. Leszczynski, Int. J. Quantum Chem., Quantum Biol. Symp. 19 (1992) 43.[14] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheese-man, V. G. Zakrzewski, J. A. Montgomery, Jr., R. E. Stratmann, J. C. Burant, S.Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J.Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clif-ford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, N. Rega, P.Salvador, J. J. Dannenberg, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Fores-man, J. Cioslowski, J. V. Ortiz, A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko,P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.Chen, M. W. Wong, J. L. Andres, C. Gonzalez, M. Head-Gordon, E. S. Replogle, andJ. A. Pople, Gaussian 98, Gaussian Inc., Pittsburgh PA, 1998.[15] A. Becke, J. Chem. Phys. 98 (1993) 5648.[16] G. Forde, A. Flood, L. Salter, G. Hill, L. Gorb and J. Leszczynski, J. Bio. Struc.Dynam. 20 (2003) 811.FIZIKA A (Zagreb) 17 (2008) 4, 151–158 157al-anber et al.: Theoretical ab initio study of the electric field . . .TEORIJSKO AB INITIO PROUČAVANJE UČINAKA ELEKTRIČNOGPOLJA NA GRAD– U I STABILNOST BAZNOG PARA G:CUčinak vanjskog električnog polja na DNA javlja se najčešće za jaka polja. Iz-vješćujemo o ishodima proučavanja učinaka vanjskog električnog polja na sastavnicebaznog para G:C polazeći od osnova teorije. Razmještaj lokalnih minimuma smooptimizirali bez ograničenja na uvjete simetrije rabeći gradijentan postupak narazini teorije funkcionala gustoće i provjerili računima drugih derivacija energije.Primijenili smo uobičajen osnovni skup CEP-31G. Izvješćujemo o promjenama raz-maka, stabilnosti i energijama med–udjelovanja. Mutacije električnim poljem moglebi se razvrstati u vǐsemjesne mutacije.158 FIZIKA A (Zagreb) 17 (2008) 4, 151–158

Teorijsko ab initio proučavanje učinaka električnog polja na građu i stabilnost baznog para G:C

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