Conformational determinants of structures in stereoisomeric cis-opened anti-benzo[a]pyrene diol epoxide adducts to adenine in DNA

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Abstract

As part of a comprehensive effort to understand the origins of the variety of structural motifs adopted by (+)- and (-)-cis- and trans-anti-[BP]-N 2-dG and -N 6-dA adducts, with the goal of contributing to the elucidation of the structure-function relationship, we present results of our comprehensive computational investigation of the C10R (+)-cis- and C10S (-)-cis-anti-[BP]-N 6-dA adducts on the nucleoside level. We have surveyed the potential energy surface of these two adducts by varying systematically, at 5°intervals in combination, the three key torsion angle determinants of conformational flexibility (χ, α', and β') in each adduct, creating 373 248 structures, and evaluating each of their energies. This has permitted us to map the entire potential energy surface of each adduct and to delineate the low-energy regions. The energy maps possess a symmetric relationship in the (+)/(-) adduct pair. This symmetry in the maps stems from the mirror image configuration of the benzylic rings in the two adducts, which produces opposite orientations of the BP residues in the C10R and C10S adducts on the nucleoside level. These opposite orientations result from primary steric hindrance between the base and the BP moiety which ensues when a (+) stereoisomer is rotated to the conformation favored by the (-) stereoisomer, and vice versa. Moreover, this steric hindrance manifested on the nucleoside level governs the structure on the duplex DNA level, accounting for observed opposite orientations in high-resolution NMR studies of C10R/C10S adduct pairs.

Original languageEnglish (US)
Pages (from-to)811-822
Number of pages12
JournalChemical Research in Toxicology
Volume13
Issue number9
DOIs
StatePublished - 2000

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Benzo(a)pyrene
Epoxy Compounds
Adenine
Nucleosides
Potential energy surfaces
Stereoisomerism
DNA
Torsional stress
Conformations
Mirrors
Nuclear magnetic resonance

ASJC Scopus subject areas

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

Cite this

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title = "Conformational determinants of structures in stereoisomeric cis-opened anti-benzo[a]pyrene diol epoxide adducts to adenine in DNA",
abstract = "As part of a comprehensive effort to understand the origins of the variety of structural motifs adopted by (+)- and (-)-cis- and trans-anti-[BP]-N 2-dG and -N 6-dA adducts, with the goal of contributing to the elucidation of the structure-function relationship, we present results of our comprehensive computational investigation of the C10R (+)-cis- and C10S (-)-cis-anti-[BP]-N 6-dA adducts on the nucleoside level. We have surveyed the potential energy surface of these two adducts by varying systematically, at 5°intervals in combination, the three key torsion angle determinants of conformational flexibility (χ, α', and β') in each adduct, creating 373 248 structures, and evaluating each of their energies. This has permitted us to map the entire potential energy surface of each adduct and to delineate the low-energy regions. The energy maps possess a symmetric relationship in the (+)/(-) adduct pair. This symmetry in the maps stems from the mirror image configuration of the benzylic rings in the two adducts, which produces opposite orientations of the BP residues in the C10R and C10S adducts on the nucleoside level. These opposite orientations result from primary steric hindrance between the base and the BP moiety which ensues when a (+) stereoisomer is rotated to the conformation favored by the (-) stereoisomer, and vice versa. Moreover, this steric hindrance manifested on the nucleoside level governs the structure on the duplex DNA level, accounting for observed opposite orientations in high-resolution NMR studies of C10R/C10S adduct pairs.",
author = "J. Tan and Geacintov, {N. E.} and S. Broyde",
year = "2000",
doi = "10.1021/tx000094q",
language = "English (US)",
volume = "13",
pages = "811--822",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "9",

}

TY - JOUR

T1 - Conformational determinants of structures in stereoisomeric cis-opened anti-benzo[a]pyrene diol epoxide adducts to adenine in DNA

AU - Tan, J.

AU - Geacintov, N. E.

AU - Broyde, S.

PY - 2000

Y1 - 2000

N2 - As part of a comprehensive effort to understand the origins of the variety of structural motifs adopted by (+)- and (-)-cis- and trans-anti-[BP]-N 2-dG and -N 6-dA adducts, with the goal of contributing to the elucidation of the structure-function relationship, we present results of our comprehensive computational investigation of the C10R (+)-cis- and C10S (-)-cis-anti-[BP]-N 6-dA adducts on the nucleoside level. We have surveyed the potential energy surface of these two adducts by varying systematically, at 5°intervals in combination, the three key torsion angle determinants of conformational flexibility (χ, α', and β') in each adduct, creating 373 248 structures, and evaluating each of their energies. This has permitted us to map the entire potential energy surface of each adduct and to delineate the low-energy regions. The energy maps possess a symmetric relationship in the (+)/(-) adduct pair. This symmetry in the maps stems from the mirror image configuration of the benzylic rings in the two adducts, which produces opposite orientations of the BP residues in the C10R and C10S adducts on the nucleoside level. These opposite orientations result from primary steric hindrance between the base and the BP moiety which ensues when a (+) stereoisomer is rotated to the conformation favored by the (-) stereoisomer, and vice versa. Moreover, this steric hindrance manifested on the nucleoside level governs the structure on the duplex DNA level, accounting for observed opposite orientations in high-resolution NMR studies of C10R/C10S adduct pairs.

AB - As part of a comprehensive effort to understand the origins of the variety of structural motifs adopted by (+)- and (-)-cis- and trans-anti-[BP]-N 2-dG and -N 6-dA adducts, with the goal of contributing to the elucidation of the structure-function relationship, we present results of our comprehensive computational investigation of the C10R (+)-cis- and C10S (-)-cis-anti-[BP]-N 6-dA adducts on the nucleoside level. We have surveyed the potential energy surface of these two adducts by varying systematically, at 5°intervals in combination, the three key torsion angle determinants of conformational flexibility (χ, α', and β') in each adduct, creating 373 248 structures, and evaluating each of their energies. This has permitted us to map the entire potential energy surface of each adduct and to delineate the low-energy regions. The energy maps possess a symmetric relationship in the (+)/(-) adduct pair. This symmetry in the maps stems from the mirror image configuration of the benzylic rings in the two adducts, which produces opposite orientations of the BP residues in the C10R and C10S adducts on the nucleoside level. These opposite orientations result from primary steric hindrance between the base and the BP moiety which ensues when a (+) stereoisomer is rotated to the conformation favored by the (-) stereoisomer, and vice versa. Moreover, this steric hindrance manifested on the nucleoside level governs the structure on the duplex DNA level, accounting for observed opposite orientations in high-resolution NMR studies of C10R/C10S adduct pairs.

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