Stereochemical origin of opposite orientations in DNA adducts derived from enantiomeric anti-benzo[a]pyrene diol epoxides with different tumorigenic potentials

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Abstract

When covalently linked to DNA, enantiomeric pairs of mirror image aromatic diol epoxides with differing tumorigenic potencies adopt opposite orientations along the DNA helix. This phenomenon has been observed by high- resolution NMR solution studies in a number of systems. Preliminary modeling efforts [Geacintov et al. (1997) Chem. Res. Toxicol. 10, 111-146) had suggested that the origin of the opposite orientation effect may be manifested even at the level of the carcinogen-modified nucleoside due to primary steric hindrance effects between the aromatic moiety and the attached base and sugar. Such a small system can be computationally investigated extensively, since a very thorough survey of the potential energy surface is feasible. Consequently; in an effort to understand the underlying origins of the opposite orientations in (+)-trans and (-)-trans-anti adduct pairs, we have undertaken an extensive investigation of the paradigm 10S (+) and 10R (- )-trans-anti-[BP]-N2-dG mononucleoside adduct pair, derived from the binding of the (+)-7R,8S,9S,10R and (-)-7S,8R,9R,10S enantiomers of 7,8-dihydro-9,- 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BP) to the exocyclic amino group of 2'-deoxyguanosine. In the present work we created 373248 different conformers for each adduct, which uniformly sampled the possible rotamers about the three flexible torsion angles governing the orientation of the base (χ) and its covalently linked BP residue (α', β') at 5°intervals, and Computed each of their energies with AMBER 4.0. The extensive results permitted us to map the potential energy surface of the molecule. Only four low-energy structural domains are found for the (+)-trans adduct and four for the (-)-trans adduct; the (+)/(-) pairs of each structural domain are mirror images, with the mirror image symmetry broken by the sugar and its attached C4'-C5' group. The most favored of these four is observed experimentally in the duplexes containing the same (+) and (-)-trans-anti-[BP]-N2-dG adducts (Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918; de los Santos et al. (1992) Biochemistry 31, 5245-5252). The origin of the opposite orientations resides in steric hindrance effects resulting from the mirror image relationship of the BP benzylic rings in the adduct pair, such that rotation of one stereoisomer into the conformational domain preferred by the other causes crowding between the base and the BP benzylic ring. Limited conformational flexibility in the torsion angle β', the one closest to the bulky BP moiety at the linkage site to guanine, plays a key role in governing the orientations in each adduct. The opposite orientation phenomenon is likely to manifest itself when the adducts are processed by cellular enzymes involved in replication, repair, and transcription and thus play a role in the differing biological outcomes stemming from the (+) and (-)-trans-anti adducts.

Original languageEnglish (US)
Pages (from-to)2956-2968
Number of pages13
JournalBiochemistry
Volume38
Issue number10
DOIs
StatePublished - Mar 9 1999

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DNA Adducts
Benzo(a)pyrene
Epoxy Compounds
Mirrors
Potential energy surfaces
Deoxyguanosine
Stereoisomerism
DNA
Guanine
Nucleosides
Sugars
Carcinogens
Biochemistry
Torsional stress
Enantiomers
Enzymes
Transcription
Repair
Nuclear magnetic resonance
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{14ed3c8e1d414af38ece407185571352,
title = "Stereochemical origin of opposite orientations in DNA adducts derived from enantiomeric anti-benzo[a]pyrene diol epoxides with different tumorigenic potentials",
abstract = "When covalently linked to DNA, enantiomeric pairs of mirror image aromatic diol epoxides with differing tumorigenic potencies adopt opposite orientations along the DNA helix. This phenomenon has been observed by high- resolution NMR solution studies in a number of systems. Preliminary modeling efforts [Geacintov et al. (1997) Chem. Res. Toxicol. 10, 111-146) had suggested that the origin of the opposite orientation effect may be manifested even at the level of the carcinogen-modified nucleoside due to primary steric hindrance effects between the aromatic moiety and the attached base and sugar. Such a small system can be computationally investigated extensively, since a very thorough survey of the potential energy surface is feasible. Consequently; in an effort to understand the underlying origins of the opposite orientations in (+)-trans and (-)-trans-anti adduct pairs, we have undertaken an extensive investigation of the paradigm 10S (+) and 10R (- )-trans-anti-[BP]-N2-dG mononucleoside adduct pair, derived from the binding of the (+)-7R,8S,9S,10R and (-)-7S,8R,9R,10S enantiomers of 7,8-dihydro-9,- 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BP) to the exocyclic amino group of 2'-deoxyguanosine. In the present work we created 373248 different conformers for each adduct, which uniformly sampled the possible rotamers about the three flexible torsion angles governing the orientation of the base (χ) and its covalently linked BP residue (α', β') at 5°intervals, and Computed each of their energies with AMBER 4.0. The extensive results permitted us to map the potential energy surface of the molecule. Only four low-energy structural domains are found for the (+)-trans adduct and four for the (-)-trans adduct; the (+)/(-) pairs of each structural domain are mirror images, with the mirror image symmetry broken by the sugar and its attached C4'-C5' group. The most favored of these four is observed experimentally in the duplexes containing the same (+) and (-)-trans-anti-[BP]-N2-dG adducts (Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918; de los Santos et al. (1992) Biochemistry 31, 5245-5252). The origin of the opposite orientations resides in steric hindrance effects resulting from the mirror image relationship of the BP benzylic rings in the adduct pair, such that rotation of one stereoisomer into the conformational domain preferred by the other causes crowding between the base and the BP benzylic ring. Limited conformational flexibility in the torsion angle β', the one closest to the bulky BP moiety at the linkage site to guanine, plays a key role in governing the orientations in each adduct. The opposite orientation phenomenon is likely to manifest itself when the adducts are processed by cellular enzymes involved in replication, repair, and transcription and thus play a role in the differing biological outcomes stemming from the (+) and (-)-trans-anti adducts.",
author = "Xie, {Xiao Ming} and Geacintov, {Nicholas E.} and Suse Broyde",
year = "1999",
month = "3",
day = "9",
doi = "10.1021/bi9825605",
language = "English (US)",
volume = "38",
pages = "2956--2968",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Stereochemical origin of opposite orientations in DNA adducts derived from enantiomeric anti-benzo[a]pyrene diol epoxides with different tumorigenic potentials

AU - Xie, Xiao Ming

AU - Geacintov, Nicholas E.

AU - Broyde, Suse

PY - 1999/3/9

Y1 - 1999/3/9

N2 - When covalently linked to DNA, enantiomeric pairs of mirror image aromatic diol epoxides with differing tumorigenic potencies adopt opposite orientations along the DNA helix. This phenomenon has been observed by high- resolution NMR solution studies in a number of systems. Preliminary modeling efforts [Geacintov et al. (1997) Chem. Res. Toxicol. 10, 111-146) had suggested that the origin of the opposite orientation effect may be manifested even at the level of the carcinogen-modified nucleoside due to primary steric hindrance effects between the aromatic moiety and the attached base and sugar. Such a small system can be computationally investigated extensively, since a very thorough survey of the potential energy surface is feasible. Consequently; in an effort to understand the underlying origins of the opposite orientations in (+)-trans and (-)-trans-anti adduct pairs, we have undertaken an extensive investigation of the paradigm 10S (+) and 10R (- )-trans-anti-[BP]-N2-dG mononucleoside adduct pair, derived from the binding of the (+)-7R,8S,9S,10R and (-)-7S,8R,9R,10S enantiomers of 7,8-dihydro-9,- 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BP) to the exocyclic amino group of 2'-deoxyguanosine. In the present work we created 373248 different conformers for each adduct, which uniformly sampled the possible rotamers about the three flexible torsion angles governing the orientation of the base (χ) and its covalently linked BP residue (α', β') at 5°intervals, and Computed each of their energies with AMBER 4.0. The extensive results permitted us to map the potential energy surface of the molecule. Only four low-energy structural domains are found for the (+)-trans adduct and four for the (-)-trans adduct; the (+)/(-) pairs of each structural domain are mirror images, with the mirror image symmetry broken by the sugar and its attached C4'-C5' group. The most favored of these four is observed experimentally in the duplexes containing the same (+) and (-)-trans-anti-[BP]-N2-dG adducts (Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918; de los Santos et al. (1992) Biochemistry 31, 5245-5252). The origin of the opposite orientations resides in steric hindrance effects resulting from the mirror image relationship of the BP benzylic rings in the adduct pair, such that rotation of one stereoisomer into the conformational domain preferred by the other causes crowding between the base and the BP benzylic ring. Limited conformational flexibility in the torsion angle β', the one closest to the bulky BP moiety at the linkage site to guanine, plays a key role in governing the orientations in each adduct. The opposite orientation phenomenon is likely to manifest itself when the adducts are processed by cellular enzymes involved in replication, repair, and transcription and thus play a role in the differing biological outcomes stemming from the (+) and (-)-trans-anti adducts.

AB - When covalently linked to DNA, enantiomeric pairs of mirror image aromatic diol epoxides with differing tumorigenic potencies adopt opposite orientations along the DNA helix. This phenomenon has been observed by high- resolution NMR solution studies in a number of systems. Preliminary modeling efforts [Geacintov et al. (1997) Chem. Res. Toxicol. 10, 111-146) had suggested that the origin of the opposite orientation effect may be manifested even at the level of the carcinogen-modified nucleoside due to primary steric hindrance effects between the aromatic moiety and the attached base and sugar. Such a small system can be computationally investigated extensively, since a very thorough survey of the potential energy surface is feasible. Consequently; in an effort to understand the underlying origins of the opposite orientations in (+)-trans and (-)-trans-anti adduct pairs, we have undertaken an extensive investigation of the paradigm 10S (+) and 10R (- )-trans-anti-[BP]-N2-dG mononucleoside adduct pair, derived from the binding of the (+)-7R,8S,9S,10R and (-)-7S,8R,9R,10S enantiomers of 7,8-dihydro-9,- 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BP) to the exocyclic amino group of 2'-deoxyguanosine. In the present work we created 373248 different conformers for each adduct, which uniformly sampled the possible rotamers about the three flexible torsion angles governing the orientation of the base (χ) and its covalently linked BP residue (α', β') at 5°intervals, and Computed each of their energies with AMBER 4.0. The extensive results permitted us to map the potential energy surface of the molecule. Only four low-energy structural domains are found for the (+)-trans adduct and four for the (-)-trans adduct; the (+)/(-) pairs of each structural domain are mirror images, with the mirror image symmetry broken by the sugar and its attached C4'-C5' group. The most favored of these four is observed experimentally in the duplexes containing the same (+) and (-)-trans-anti-[BP]-N2-dG adducts (Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918; de los Santos et al. (1992) Biochemistry 31, 5245-5252). The origin of the opposite orientations resides in steric hindrance effects resulting from the mirror image relationship of the BP benzylic rings in the adduct pair, such that rotation of one stereoisomer into the conformational domain preferred by the other causes crowding between the base and the BP benzylic ring. Limited conformational flexibility in the torsion angle β', the one closest to the bulky BP moiety at the linkage site to guanine, plays a key role in governing the orientations in each adduct. The opposite orientation phenomenon is likely to manifest itself when the adducts are processed by cellular enzymes involved in replication, repair, and transcription and thus play a role in the differing biological outcomes stemming from the (+) and (-)-trans-anti adducts.

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