Abstract
The chemical carcinogen (+)-anti BPDE preferentially binds covalently to the guanine base in the minor groove of DNA. Fluorescence spectroscopic studies have shown that the BPDE molecules bound to DNA can interact in their photo-excited state giving strong excimer fluorescence when bound to poly(dGdC) · poly(dGdC). It was suggested that the formation of such excited state complexes is most probable when the two (+)-anti-BPDE bind to guanines of adjacent base pairs on the two different strands of the DNA. In the present work a model for such an excimer forming DNA-BPDE double adduct system has been constructed and shown to be stable over a 300 ps molecular dynamics simulation in a water box. The model is a d(CG)3 · d(CG)3 molecule with two BPDE molecules bound to the guanines at the 4th position on each strand, located in the minor groove and each oriented towards the 5′ end of the modified strand, respectively. The results of 300 ps MD simulation show that the two BPDE chromophores exhibited on the average a relative geometry favourable for excimer formation. The local structure at the adduct position was considerably distorted and the helix axis was bent. The modified bases were found to be paired through a stable single non-Watson Crick type of hydrogen bond.
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Aggarwal AK, Islam SA, Neidle S (1983) Computer modelling studies of the covalent interactions between DNA and the enantiomers of anti-7,8-diol, 9,10-epoxy-benzo(a)pyrene. J Biomol Struct Dynam 1:873–881
Baum EJ (1978) Occurrence and surveillance of polycyclic aromatic hydrocarbons. In: Polycyclic Aromatic Hydrocarbons and Cancer. Vol 1, Gelboin HV Ts'o POP (eds) Academic Press, New York, pp 45–62
Birks JB (1980) Photophysics of Aromatic Molecules Wiley, New York
Brooks R, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) A program for macromolecular energy, minimization and dynamics calculations. J Comput Chem 4:187–217
Carothers AM, Grunberger D (1990) DNA base changes in benzo(a) pyrene diol epoxide induced dihydrofolate reductase mutants of Chinese hamster ovary cells. Carcinogenesis 11: 189–192
Chen X, Ramakrishnan B, Rao ST, Sundaralingam M (1994) Binding of two distamycin A molecules in the minor groove of an alternating B-DNA duplex. Struct Biol 1:169–175
Cooper CS, Grover PL, Sims P (1983) The metabolism and activation of benzo(a) pyrene. In: Bridges JW, Chasseaud LF (eds) Prog Drug Metab 7:295–396
Cosman M, de los Santos C, Fiala R, Hingerty BE, Singh SB, Ibanez V, Margulis LA, Live D, Geacintov NE, Broyde S, Patel DJ (1992) Solution conformation of the major adduct between the carcinogen (+)-anti-benzo(a) pyrene diol epoxide and DNA. Proc Natl Acad Sci, USA 89:1914–1918
de los Santos C, Cosman M, Hingerty BE, Ibanez V Margulis LA, Geacintov NE, Broyde S, Patel DJ (1992) Influence of benzo(a)pyrene diol epoxide chirality on solution conformations of DNA covalent adducts: the (s-)-trans -anti- (BP)G.C adduct structure and comparison with the (+)-trans-anti- (BP)G.C enantiomer. Biochemistry 31:5245–5252
Dipple A (1985) Polycyclic aromatic hydrocarbon carcinogenesis. introduction. In: Polycyclic Hydrocarbons and Carcinogenesis: Harvey RG (ed) ACS Symposium series 238; American Chemical Society: Washington DC, pp 1–17
Eriksson M, Norden B, Jernström B, Graslund A (1988) Binding geometries of benzo(a)pyrene-diol epoxide isomers covalently bound to DNA. Orientational distribution. Biochemistry 27: 1213–1221
Eriksson M, Norden B, Jernström B, Gräslund A, Lycksell P-O (1988) Observation of excimer formation in the covalent adducts of 9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene-7,8-diol with poly(dG-dC). J Chem Soc Chem Commun 1988:211–212
Eriksson M, Eriksson S, Jernström B, Norden B, Gräslund A (1990) Excimer fluorescence of (+)-anti-benzo(a) pyrene diol epoxide covalently bound to poly (dG-dC): Structural Implications. Biopolymers 29: 1249–1258
Eriksson M, Kim SK, Sen S, Gräslund A, Jernström B, Norden B (1993) Location of excimer-forming adducts of (+)-anti-benzo(a) pyrene diol epoxide in DNA. J Am Chem Soc 115:1639–1644
Geacintov NE (1988) Mechanisms of reaction of polycyclic aromatic epoxide derivatives with nucleic acids. In: Polycyclic Aromatic Hydrocarbon Carcinogenesis: Structure-Activity Relationships vol. 2, Yang SK, Silverman BD (eds) CRC: Boca Raton, FL, pp 181–206
Geacimov NE, Gagliano AG, Ivanovic V Weinstein IB (1978) Electric linear dichroism study on the orientation of benzo(a) pyrene-7,8-dihydrodio19,10-epoxide covalent adduct to DNA. Biochemistry 17:5256–5262
Gräslund A, Jernström B (1989) DNA-carcinogen interaction: covalent DNAadducts of benz(a) pyrene 7,8-dihydrodiol 9,10-epoxides studied by biochemical and biophysical techniques. Q Rev Biophys 22:1–37
Gräslund A, Kim SK, Eriksson S, Norden B, Jernström B (1992) Dynamics of benzo(a)pyrene diol epoxide adducts in poly(dGdC) · (dG-dC) studied by synchrotron excited fluorescence polarization anisotropy decay. Biophys Chem 44:21–28
Grimmer G, Pott F (1983) In: Environmental Carcinogens: Polycyclic Aromatic Hydrocarbons, Grimmer G (Ed) CRC Press, Boca Raton, FL, p 61
Herzyk P, Neidle S, Goodfellow JM (1992) Conformations and dynamics of drug-DNA interactions. J Biomol Struct Dynam 10: 97–139
Hingerty BE, Broyde S (1985) Carcinogen - base stacking and base — base stacking in dCpdG modified by (+) and (−) anti-BPDE. Biopolymers 24:2279–2299
Jerina DM, Chadha A, Cheh A, Schurdak ME, Wood AW, Sayer JM (1991) In: Biological Reactive Intermediates. Witmer CM, Snyder R, Jollow DJ, Kalf GS, Kocsis JJ, Sipes IG (eds) Plenum Press, New York, p 533
Jernström B, Gräslund A (1994) Covalent binding of benzo(a) pyrene 7,8-dihydrodiol 9,10-epoxides to DNA: molecular structures, induced mutations and biological consequences. Biophys Chem 49:185–199
Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935
Mao B, Li B, Li D, Geacintov NE (1993) Characteristics of stereospecific N2-dG-BPDE-oligonucleotide adducts: flexible hinge joints and differences in exonuclease digestion efficiencies. J Biomol Struct Dynam 10: a123
Neidle S, Subbiah A, Kuroda R, Cooper CS (1982) Molecular structure of (±)-7,8,9,10 tetrahydroxy-7,8,9,10-tetrahydrobenzo(a) pyrene determined by X-ray crystallography. Cancer Res 42: 3766–3768
Nilsson L, Karplus M (1986) Energy functions for energy minimization and dynamics of nucleic acids. J Comput Chem 7:591–616
Prout VCK, Wright JD (1968) Betrachtungen zu den Kristallstrukturen von Electronen-donor-acceptor-komplexen. Angew Chem 80:688–697
Rao SN, Lybrand T, Michau D, Jerina DM, Kollman PA (1989) Molecular mechanics simulations on covalent complexes between polycyclic carcinogens and B-DNA. Carcinogenesis 10:27–38
Singh SB, Hingerty BE, Singh UC, Greenberg JP, Geacintov NE, Broyde S (1991) Structures of the (+)- and (-)-trans- 7, 8-dihydroxy-anti-9,10-epoxy-7,8,9,10-hydrobenzo(a) pyrene adducts to guanine-N2 in a duplex dodecamer. Cancer Res 51:3482–3492
Thakker DR, Yagi H, Levin W, Wood AW, Conney AH, Jerina DM (1985) Polycyclic aromatic hydrocarbons: metabolic activation to ultimate carcinogens. In: Bioactivation of Foreign Compounds. Anders MW (ed) Academic Press, New York, pp 177–242
Turro NJ (1978) Modern Molecular Photochemistry. The Benjamin Cumming's, Menlo Park, pp 135–146
Undeman O, Lycksell PO, Graslund A, Astlind T, Ehrenberg A, Jernström B, Tjerneld F, Norden B (1983) Covalent complexes of DNA and two stereoisomers of benzo(a) pyrene-7,8-diyhdrodiol-9,10-epoxide studied by fluorescence and linear dichroism. Cancer Res 43:1851–1860
van Gunsteren WE, Berendsen HJC (1977) Algorithms for macromolecular dynamics and constraint dynamics. Mol Phys 34: 1311–1327
Weinstein IB, Jeffrey AM, Leffler S, Pulkrabek P, Yamasaki H, Grunberger D (1978) Interactions between polycylic hydrocarbons and cellular macromolecules. In: Polycyclic Hydrocarbons and Cancer, vol 2. Gelboin HV, Ts'o POP (eds) Academic Press, New York, pp 3–36
Weston A, Newman MJ, Mann DL, Brooks BR (1990) Molecular mechanisms and antibody binding in the structural analysis of polycyclic aromatic hydrocarbon-diol-epoxide-DNA adducts. Carcinogenesis 11:859–864
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Correspondence to: A. Gräslund
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Sent, S., Graslund, A. Molecular dynamics simulations of excimer forming (+)-anti-BPDE-DNA adducts in aqueous solution. Eur Biophys J 23, 399–406 (1995). https://doi.org/10.1007/BF00196826
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DOI: https://doi.org/10.1007/BF00196826