Origins of conformational differences between cis and trans DNA adducts derived from enantiomeric anti-benzo[a]pyrene diol epoxides

Research output: Contribution to journalArticle

Abstract

The two enantiomeric metabolites of the carcinogen precursor benzo[a]pyrene, (+)- and (-)-anti-BPDE [(7R,8S)-dihydroxy-(9S,10R)-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene and the corresponding 7S,8R,9R,10S enantiomer, respectively], bind predominantly to the exocyclic amino groups of dG residues in double-stranded DNA by either cis or trans addition to yield four stereoisomerically distinct [BP]-N2-dG adducts. Both the 10S (+)- trans and 10R (-)-trans adducts assume minor groove conformations in normal, full duplexes, but with opposite 5' or 3' orientations, respectively, relative to the modified strand. In contrast, the 10R (+)-cis and 10S (-)- cis adducts assume oppositely oriented base-displaced intercalative conformations in normal duplexes, with the inserted pyrenyl residues pointing toward the major groove in the (+)-cis isomer and toward the minor groove in the (-)-cis isomer. A BPDE-modified nucleoside is a small system which can be studied by computational methods with a very thorough survey of the potential energy surface. To investigate conformational differences between cis and trans adducts, and to elucidate origins governing the opposite orientations of these (+)- and (-)-diol epoxide adducts, we have carried out extensive investigations of the (+)- and (-)-trans-anti-and (+)- and (-)-cis-anti- [BP]-N2-dG deoxynucleoside adduct pairs. We report results for the (+)- and (-)-cis-anti pair, and compare them with the (+)- and (-)-trans-anti adducts. We created 373 248 different conformers for each adduct, which uniformly sampled at 5°intervals the possible rotamers about three flexible torsion angles governing base (χ) and carcinogen (α' and β') orientations, and computed each of their energies. The potential energy surface of the molecule was then mapped from these results. While four potential energy wells or structural domains are found for the (+)-trans adduct and four for the (-)- trans adduct, only two of these four domains are favored for each of the two cis adducts. In both cis and trans adducts, the (+)/(-) pairs of each structural domain are nearly mirror images. The most favored of the domains in both cis and trans adducts is observed experimentally in the duplexes containing each of these [BP]-N2-dG lesions. The opposite orientations in both cis and trans adducts stem from steric crowding at the benzylic ring, engendered when a (+) stereoisomer is rotated into the analogous conformation of its (-) partner, and vice versa. Furthermore, the key role of the difference in absolute configuration between trans and cis adducts at the hydroxyls of C9 and C8 in governing conformational preferences and flexibility is delineated. Cis adducts are less conformationally flexible than trans adducts because they are inherently more sterically crowded, with C9-OH and C8-OH on the same side of the benzylic ring as guanine and sugar, while they are on the opposite side of the benzylic ring in the trans adducts. Consequently, the cis adducts inherently favor less the minor groove position adopted by trans adducts in DNA duplexes because the C9-OH and C8- OH are directed inward into the minor groove in the cis adducts. In the trans adducts, the C9-OH and C8-OH are directed outward, away from the interior of the minor groove. Observed differential processing of these four adducts by replication, repair, and transcription enzymes may well stem from their differing conformational preferences.

Original languageEnglish (US)
Pages (from-to)597-609
Number of pages13
JournalChemical Research in Toxicology
Volume12
Issue number7
DOIs
StatePublished - 1999

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7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
DNA Adducts
Benzo(a)pyrene
Epoxy Compounds
Carcinogens
Conformations
Potential energy surfaces
Isomers
Stereoisomerism
Guanine
Nucleosides
Hydroxyl Radical
Enantiomers
DNA
Transcription
Metabolites
Computational methods
Potential energy
Sugars
Torsional stress

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Health, Toxicology and Mutagenesis
  • Drug Discovery
  • Toxicology

Cite this

@article{c021dcba1c944f6d9bc6b765ffa3f534,
title = "Origins of conformational differences between cis and trans DNA adducts derived from enantiomeric anti-benzo[a]pyrene diol epoxides",
abstract = "The two enantiomeric metabolites of the carcinogen precursor benzo[a]pyrene, (+)- and (-)-anti-BPDE [(7R,8S)-dihydroxy-(9S,10R)-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene and the corresponding 7S,8R,9R,10S enantiomer, respectively], bind predominantly to the exocyclic amino groups of dG residues in double-stranded DNA by either cis or trans addition to yield four stereoisomerically distinct [BP]-N2-dG adducts. Both the 10S (+)- trans and 10R (-)-trans adducts assume minor groove conformations in normal, full duplexes, but with opposite 5' or 3' orientations, respectively, relative to the modified strand. In contrast, the 10R (+)-cis and 10S (-)- cis adducts assume oppositely oriented base-displaced intercalative conformations in normal duplexes, with the inserted pyrenyl residues pointing toward the major groove in the (+)-cis isomer and toward the minor groove in the (-)-cis isomer. A BPDE-modified nucleoside is a small system which can be studied by computational methods with a very thorough survey of the potential energy surface. To investigate conformational differences between cis and trans adducts, and to elucidate origins governing the opposite orientations of these (+)- and (-)-diol epoxide adducts, we have carried out extensive investigations of the (+)- and (-)-trans-anti-and (+)- and (-)-cis-anti- [BP]-N2-dG deoxynucleoside adduct pairs. We report results for the (+)- and (-)-cis-anti pair, and compare them with the (+)- and (-)-trans-anti adducts. We created 373 248 different conformers for each adduct, which uniformly sampled at 5°intervals the possible rotamers about three flexible torsion angles governing base (χ) and carcinogen (α' and β') orientations, and computed each of their energies. The potential energy surface of the molecule was then mapped from these results. While four potential energy wells or structural domains are found for the (+)-trans adduct and four for the (-)- trans adduct, only two of these four domains are favored for each of the two cis adducts. In both cis and trans adducts, the (+)/(-) pairs of each structural domain are nearly mirror images. The most favored of the domains in both cis and trans adducts is observed experimentally in the duplexes containing each of these [BP]-N2-dG lesions. The opposite orientations in both cis and trans adducts stem from steric crowding at the benzylic ring, engendered when a (+) stereoisomer is rotated into the analogous conformation of its (-) partner, and vice versa. Furthermore, the key role of the difference in absolute configuration between trans and cis adducts at the hydroxyls of C9 and C8 in governing conformational preferences and flexibility is delineated. Cis adducts are less conformationally flexible than trans adducts because they are inherently more sterically crowded, with C9-OH and C8-OH on the same side of the benzylic ring as guanine and sugar, while they are on the opposite side of the benzylic ring in the trans adducts. Consequently, the cis adducts inherently favor less the minor groove position adopted by trans adducts in DNA duplexes because the C9-OH and C8- OH are directed inward into the minor groove in the cis adducts. In the trans adducts, the C9-OH and C8-OH are directed outward, away from the interior of the minor groove. Observed differential processing of these four adducts by replication, repair, and transcription enzymes may well stem from their differing conformational preferences.",
author = "Xie, {Xiao Ming} and Nicholas Geacintov and Suse Broyde",
year = "1999",
doi = "10.1021/tx990021a",
language = "English (US)",
volume = "12",
pages = "597--609",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Origins of conformational differences between cis and trans DNA adducts derived from enantiomeric anti-benzo[a]pyrene diol epoxides

AU - Xie, Xiao Ming

AU - Geacintov, Nicholas

AU - Broyde, Suse

PY - 1999

Y1 - 1999

N2 - The two enantiomeric metabolites of the carcinogen precursor benzo[a]pyrene, (+)- and (-)-anti-BPDE [(7R,8S)-dihydroxy-(9S,10R)-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene and the corresponding 7S,8R,9R,10S enantiomer, respectively], bind predominantly to the exocyclic amino groups of dG residues in double-stranded DNA by either cis or trans addition to yield four stereoisomerically distinct [BP]-N2-dG adducts. Both the 10S (+)- trans and 10R (-)-trans adducts assume minor groove conformations in normal, full duplexes, but with opposite 5' or 3' orientations, respectively, relative to the modified strand. In contrast, the 10R (+)-cis and 10S (-)- cis adducts assume oppositely oriented base-displaced intercalative conformations in normal duplexes, with the inserted pyrenyl residues pointing toward the major groove in the (+)-cis isomer and toward the minor groove in the (-)-cis isomer. A BPDE-modified nucleoside is a small system which can be studied by computational methods with a very thorough survey of the potential energy surface. To investigate conformational differences between cis and trans adducts, and to elucidate origins governing the opposite orientations of these (+)- and (-)-diol epoxide adducts, we have carried out extensive investigations of the (+)- and (-)-trans-anti-and (+)- and (-)-cis-anti- [BP]-N2-dG deoxynucleoside adduct pairs. We report results for the (+)- and (-)-cis-anti pair, and compare them with the (+)- and (-)-trans-anti adducts. We created 373 248 different conformers for each adduct, which uniformly sampled at 5°intervals the possible rotamers about three flexible torsion angles governing base (χ) and carcinogen (α' and β') orientations, and computed each of their energies. The potential energy surface of the molecule was then mapped from these results. While four potential energy wells or structural domains are found for the (+)-trans adduct and four for the (-)- trans adduct, only two of these four domains are favored for each of the two cis adducts. In both cis and trans adducts, the (+)/(-) pairs of each structural domain are nearly mirror images. The most favored of the domains in both cis and trans adducts is observed experimentally in the duplexes containing each of these [BP]-N2-dG lesions. The opposite orientations in both cis and trans adducts stem from steric crowding at the benzylic ring, engendered when a (+) stereoisomer is rotated into the analogous conformation of its (-) partner, and vice versa. Furthermore, the key role of the difference in absolute configuration between trans and cis adducts at the hydroxyls of C9 and C8 in governing conformational preferences and flexibility is delineated. Cis adducts are less conformationally flexible than trans adducts because they are inherently more sterically crowded, with C9-OH and C8-OH on the same side of the benzylic ring as guanine and sugar, while they are on the opposite side of the benzylic ring in the trans adducts. Consequently, the cis adducts inherently favor less the minor groove position adopted by trans adducts in DNA duplexes because the C9-OH and C8- OH are directed inward into the minor groove in the cis adducts. In the trans adducts, the C9-OH and C8-OH are directed outward, away from the interior of the minor groove. Observed differential processing of these four adducts by replication, repair, and transcription enzymes may well stem from their differing conformational preferences.

AB - The two enantiomeric metabolites of the carcinogen precursor benzo[a]pyrene, (+)- and (-)-anti-BPDE [(7R,8S)-dihydroxy-(9S,10R)-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene and the corresponding 7S,8R,9R,10S enantiomer, respectively], bind predominantly to the exocyclic amino groups of dG residues in double-stranded DNA by either cis or trans addition to yield four stereoisomerically distinct [BP]-N2-dG adducts. Both the 10S (+)- trans and 10R (-)-trans adducts assume minor groove conformations in normal, full duplexes, but with opposite 5' or 3' orientations, respectively, relative to the modified strand. In contrast, the 10R (+)-cis and 10S (-)- cis adducts assume oppositely oriented base-displaced intercalative conformations in normal duplexes, with the inserted pyrenyl residues pointing toward the major groove in the (+)-cis isomer and toward the minor groove in the (-)-cis isomer. A BPDE-modified nucleoside is a small system which can be studied by computational methods with a very thorough survey of the potential energy surface. To investigate conformational differences between cis and trans adducts, and to elucidate origins governing the opposite orientations of these (+)- and (-)-diol epoxide adducts, we have carried out extensive investigations of the (+)- and (-)-trans-anti-and (+)- and (-)-cis-anti- [BP]-N2-dG deoxynucleoside adduct pairs. We report results for the (+)- and (-)-cis-anti pair, and compare them with the (+)- and (-)-trans-anti adducts. We created 373 248 different conformers for each adduct, which uniformly sampled at 5°intervals the possible rotamers about three flexible torsion angles governing base (χ) and carcinogen (α' and β') orientations, and computed each of their energies. The potential energy surface of the molecule was then mapped from these results. While four potential energy wells or structural domains are found for the (+)-trans adduct and four for the (-)- trans adduct, only two of these four domains are favored for each of the two cis adducts. In both cis and trans adducts, the (+)/(-) pairs of each structural domain are nearly mirror images. The most favored of the domains in both cis and trans adducts is observed experimentally in the duplexes containing each of these [BP]-N2-dG lesions. The opposite orientations in both cis and trans adducts stem from steric crowding at the benzylic ring, engendered when a (+) stereoisomer is rotated into the analogous conformation of its (-) partner, and vice versa. Furthermore, the key role of the difference in absolute configuration between trans and cis adducts at the hydroxyls of C9 and C8 in governing conformational preferences and flexibility is delineated. Cis adducts are less conformationally flexible than trans adducts because they are inherently more sterically crowded, with C9-OH and C8-OH on the same side of the benzylic ring as guanine and sugar, while they are on the opposite side of the benzylic ring in the trans adducts. Consequently, the cis adducts inherently favor less the minor groove position adopted by trans adducts in DNA duplexes because the C9-OH and C8- OH are directed inward into the minor groove in the cis adducts. In the trans adducts, the C9-OH and C8-OH are directed outward, away from the interior of the minor groove. Observed differential processing of these four adducts by replication, repair, and transcription enzymes may well stem from their differing conformational preferences.

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