Solution conformation of the (+)-trans-anti-[BPh]dA adduct opposite dT in a DNA duplex: intercalation of the covalently attached benzo[c]phenanthrene to the 5'-side of the adduct site without disruption of the modified base pair.

Benzo[c]phenanthrene diol epoxide can covalently bind to the exocyclic amino group of deoxyadenosine to generate [BPh]dA adducts where the polycyclic aromatic hydrocarbon is attached to the major groove edge of DNA. This paper reports on NMR-energy minimization structural studies of the (+)-trans-anti-[BPh]dA adduct positioned opposite dT in the sequence context d(C5-[BPh]A6-C7).d-(G16-T17-G18) at the 11-mer duplex level. The exchangeable and nonexchangeable protons of the benzo[c]phenanthrenyl moiety and the nucleic acid were assigned following analysis of two-dimensional NMR data sets in H2O and D2O solution. The solution structure of the (+)-trans-anti-[BPh]dA.dT 11-mer duplex has been determined by incorporating intramolecular and intermolecular proton-proton distances defined by upper and lower bounds deduced from NOESY data sets as restraints in energy minimization computations. The covalently attached benzo[c]phenanthrene ring intercalates to the 5'-side of the [BPh]-dA6 lesion site without disruption of the flanking Watson-Crick dC5.dG18 and [BPh]dA6.dT17 base pairs. The observed buckling of the intercalation cavity reflects the selective overlap of the intercalated phenanthrenyl ring with dT17 and dG18 bases on the unmodified strand. The structure provides new insights into how a polycyclic aromatic hydrocarbon covalently attached to the major groove edge of deoxyadenosine can still unidirectionally intercalate into the helix without disruption of the modified base pair. Our study establishes that among the contributing factors are a propeller-twisted [BPh]dA6.dT17 base pair, displacement of the carcinogen-DNA linkage bond from the plane of the dA6 base, the specific pucker adopted by the benzylic ring, and the propeller-like nonplanar geometry for the aromatic phenanthrenyl ring system. Our combined experimental-computational studies to date have now identified three structural motifs adopted by covalent polycyclic aromatic hydrocarbon-DNA adducts with their distribution determined by the chiral characteristics of individual stereoisomers and by whether the covalent adducts are generated at the minor or the major groove edge of the helix.

[1]  D. Patel,et al.  Solution conformation of the (+)-cis-anti-[BP]dG adduct in a DNA duplex: intercalation of the covalently attached benzo[a]pyrenyl ring into the helix and displacement of the modified deoxyguanosine. , 1993, Biochemistry.

[2]  D. Patel,et al.  Solution structure of the covalent sterigmatocystin-DNA adduct. , 1992, Biochemistry.

[3]  D. Jerina,et al.  Identification of individual benzo[c]phenanthrene dihydrodiol epoxide-DNA adducts by the 32P-postlabeling assay. , 1992, Chemical research in toxicology.

[4]  D. Patel,et al.  Influence of benzo[a]pyrene diol epoxide chirality on solution conformations of DNA covalent adducts: the (-)-trans-anti-[BP]G.C adduct structure and comparison with the (+)-trans-anti-[BP]G.C enantiomer. , 1992, Biochemistry.

[5]  D. Patel,et al.  Solution conformation of the major adduct between the carcinogen (+)-anti-benzo[a]pyrene diol epoxide and DNA. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Jerina,et al.  Mutagenic specificities of four stereoisomeric benzo[c]phenanthrene dihydrodiol epoxides. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. Wang,et al.  Formaldehyde cross-links daunorubicin and DNA efficiently: HPLC and X-ray diffraction studies. , 1992, Biochemistry.

[8]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[9]  U. Singh,et al.  Structures of the (+)- and (-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyre ne adducts to guanine-N2 in a duplex dodecamer. , 1991, Cancer research.

[10]  T. Harris,et al.  Intercalation of aflatoxin B1 in two oligodeoxynucleotide adducts: comparative 1H NMR analysis of d(ATCAFBGAT).d(ATCGAT) and d(ATAFBGCAT)2. , 1990, Biochemistry.

[11]  N. Geacintov,et al.  Preparation and isolation of adducts in high yield derived from the binding of two benzo[a]pyrene-7,8-dihydroxy-9,10-oxide stereoisomers to the oligonucleotide d(ATATGTATA). , 1990, Carcinogenesis.

[12]  S. Amin,et al.  An improved synthesis of anti-benzo[c]phenanthrene-3,4-diol 1,2-epoxide via 4-methoxybenzo[c]phenanthrene , 1990 .

[13]  G. Chang,et al.  Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics , 1990 .

[14]  D. Patel,et al.  NMR and computational characterization of the N-(deoxyguanosin-8-yl)aminofluorene adduct [(AF)G] opposite adenosine in DNA: (AF)G[syn].A[anti] pair formation and its pH dependence. , 1989, Biochemistry.

[15]  J. M. Roman,et al.  DNA adducts from carcinogenic and noncarcinogenic enantiomers of benzo[a]pyrene dihydrodiol epoxide. , 1989, Chemical research in toxicology.

[16]  T. Hayden,et al.  Prediction of DNA structure from sequence: A build‐up technique , 1989, Biopolymers.

[17]  D. Jerina,et al.  Mutagenic specificity of a potent carcinogen, benzo[c]phenanthrene (4R,3S)-dihydrodiol (2S,1R)-epoxide, which reacts with adenine and guanine in DNA. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. W. Hilbers,et al.  Nucleic acids and nuclear magnetic resonance. , 1988, European journal of biochemistry.

[19]  D. Jerina,et al.  Stereochemical specificity in the metabolic activation of benzo(c)phenanthrene to metabolites that covalently bind to DNA in rodent embryo cell cultures. , 1987, Cancer research.

[20]  D. Jerina,et al.  Optically active benzo[c]phenanthrene diol epoxides bind extensively to adenine in DNA , 1987, Nature.

[21]  L. Pannell,et al.  Chemical characterization of DNA adducts derived from the configurationnally isomeric benzo[c]phenanthrene-3,4-diol 1,2-epoxides , 1987 .

[22]  D. Jerina,et al.  Tumorigenicity of optical isomers of the diastereomeric bay-region 3,4-diol-1,2-epoxides of benzo(c)phenanthrene in murine tumor models. , 1986, Cancer research.

[23]  D. Jerina,et al.  Stereoselective metabolism of the (+)-(S,S)- and (-)-(R,R)-enantiomers of trans-3,4-dihydroxy-3,4-dihydrobenzo[c]-phenanthrene by rat and mouse liver microsomes and by a purified and reconstituted cytochrome P-450 system. , 1986, The Journal of biological chemistry.

[24]  B. Hingerty,et al.  Carcinogen–base stacking and base–base stacking in dCpdG modified by (+) and (−) anti‐BPDE , 1985, Biopolymers.

[25]  J. Glusker,et al.  The bay-region geometry of some 5-methylchrysenes: steric effects in 5,6- and 5,12-dimethylchrysenes. , 1984, Carcinogenesis.

[26]  D. Jerina,et al.  Mutagenicity of the enantiomers of the diastereomeric bay-region benzo(c)phenanthrene 3,4-diol-1,2-epoxides in bacterial and mammalian cells. , 1983, Cancer research.

[27]  W. Olson,et al.  Theoretical studies of nucleic acid interactions. I. Estimates of conformational mobility in intercalated chains , 1983, Biopolymers.

[28]  D. Jerina,et al.  Synthesis and assignment of absolute configuration to the trans 3,4-dihydrodiols and 3,4-diol-1,2-epoxides of benzo[c]phenanthrene , 1983 .

[29]  A. Conney,et al.  Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. , 1982, Cancer research.

[30]  S. Neidle,et al.  Molecular structure of (+/-)-7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene determined by x-ray crystallography. , 1982, Cancer research.

[31]  A. Rich,et al.  Right-handed and left-handed DNA: studies of B- and Z-DNA by using proton nuclear Overhauser effect and P NMR. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H R Drew,et al.  Structure of a B-DNA dodecamer: conformation and dynamics. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[33]  R. Ornstein,et al.  Energetics of intercalation specificity. I. Backbone unwinding , 1979, Biopolymers.

[34]  E. Miller.  Some current perspectives on chemical carcinogenesis in humans and experimental animals: Presidential Address. , 1978, Cancer research.

[35]  A. Bjørseth,et al.  Polycyclic aromatic hydrocarbons in long-range transported aerosols , 1977, Nature.

[36]  S. Arnott,et al.  Models of triple-stranded polynucleotides with optimised stereochemistry. , 1976, Nucleic acids research.

[37]  M. Sundaralingam,et al.  Conformational analysis of the sugar ring in nucleosides and nucleotides. A new description using the concept of pseudorotation. , 1972, Journal of the American Chemical Society.

[38]  Khorana Hg,et al.  Studies on polynucleotides. X. Enzymic degradation. Some properties and mode of action of spleen phosphodiesterase. , 1961 .