Principles governing conformations in stereoisomeric adducts of Bay region benzo[a]pyrene diol epoxides to adenine in DNA: Steric and hydrophobic effects are dominant

Research output: Contribution to journalArticle

Abstract

The stereochemical properties of ligands that form covalent adducts with DNA have profound effects on their biochemical functions. Differing absolute configurations of substituents about chiral carbon atoms can lead to strikingly different conformations when such stereoisomeric compounds bind to DNA. The environmental chemical carcinogen, benzo[a]pyrene (BP), provides a remarkable example of such stereochemical effects. Metabolic activation of benzo[a]pyrene leads to a pair of enantiomers, (+)-(7R,8S,9S,10R)-7,8- dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its (-)- (7S,SR,9R,10S) mirror-image, known as (+)- and (-)-anti-BPDE. Both (+)- and (-)-anti-BPDE react with the amino group of adenine in DNA via trans epoxide opening, yielding a pair of stereochemically distinct trans-anti- benzo[a]pyrenyl adducts, whose possible role in chemical carcinogenesis is of great interest. High-resolution NMR solution studies (Schurter et al. Biochemistry 1995, 34, 1364-75; Yeh et al. Biochemistry 1995, 34, 13570-81; Zegar et al. Biochemistry 1996, 35, 621224; Schwartz et al., Biochemistry 1997, 36, 11069-76) have revealed that in the 10S (+)- and 10R (-)-trans-anti adducts, the BP is classically intercalated, residing on the 3'-side of the modified adenine in the (+)trans-anti adduct and on the 5'-side in the (-) stereoisomer. To elucidate the stereochemical principles underlying these conformational preferences, an extensive survey of the potential energy surface of each modified nucleoside was carried out, in which the energy of 373,248 structures for each adduct was computed using AMBER 5.0. Our results reveal near mirror image symmetries in the four pairs of low-energy structural domains of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts, which is rooted in the exact enantiomeric relationship of the BPDE precursors, and accounts for the opposite orientations observed in solution. Steric hindrance prevents an R isomer from assuming the orientation favored by the S isomer, and vice versa. The NMR solution structures of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts in DNA adopt conformations which are in the low-energy domains computed for the nucleoside adducts. In addition, we find that the preference for classical intercalation over a major groove position for the pyrenyl ring system in the [BP]-N 6-dA adducts stems from the advantage of burying the hydrophobic pyrenyl moiety within the helix rather than having it exposed in the large major groove.

Original languageEnglish (US)
Pages (from-to)3021-3032
Number of pages12
JournalJournal of the American Chemical Society
Volume122
Issue number13
DOIs
StatePublished - Apr 5 2000

Fingerprint

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Biochemistry
Benzo(a)pyrene
Epoxy Compounds
Pyrene
Adenine
Conformations
DNA
Nucleosides
Isomers
Mirrors
Nuclear magnetic resonance
Environmental Carcinogens
Nucleic Acid Conformation
Carcinogens
Potential energy surfaces
Stereoisomerism
Enantiomers
DNA Adducts
Intercalation

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

@article{3454a2c2a2ec4381bbd7fe2eed19f6c0,
title = "Principles governing conformations in stereoisomeric adducts of Bay region benzo[a]pyrene diol epoxides to adenine in DNA: Steric and hydrophobic effects are dominant",
abstract = "The stereochemical properties of ligands that form covalent adducts with DNA have profound effects on their biochemical functions. Differing absolute configurations of substituents about chiral carbon atoms can lead to strikingly different conformations when such stereoisomeric compounds bind to DNA. The environmental chemical carcinogen, benzo[a]pyrene (BP), provides a remarkable example of such stereochemical effects. Metabolic activation of benzo[a]pyrene leads to a pair of enantiomers, (+)-(7R,8S,9S,10R)-7,8- dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its (-)- (7S,SR,9R,10S) mirror-image, known as (+)- and (-)-anti-BPDE. Both (+)- and (-)-anti-BPDE react with the amino group of adenine in DNA via trans epoxide opening, yielding a pair of stereochemically distinct trans-anti- benzo[a]pyrenyl adducts, whose possible role in chemical carcinogenesis is of great interest. High-resolution NMR solution studies (Schurter et al. Biochemistry 1995, 34, 1364-75; Yeh et al. Biochemistry 1995, 34, 13570-81; Zegar et al. Biochemistry 1996, 35, 621224; Schwartz et al., Biochemistry 1997, 36, 11069-76) have revealed that in the 10S (+)- and 10R (-)-trans-anti adducts, the BP is classically intercalated, residing on the 3'-side of the modified adenine in the (+)trans-anti adduct and on the 5'-side in the (-) stereoisomer. To elucidate the stereochemical principles underlying these conformational preferences, an extensive survey of the potential energy surface of each modified nucleoside was carried out, in which the energy of 373,248 structures for each adduct was computed using AMBER 5.0. Our results reveal near mirror image symmetries in the four pairs of low-energy structural domains of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts, which is rooted in the exact enantiomeric relationship of the BPDE precursors, and accounts for the opposite orientations observed in solution. Steric hindrance prevents an R isomer from assuming the orientation favored by the S isomer, and vice versa. The NMR solution structures of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts in DNA adopt conformations which are in the low-energy domains computed for the nucleoside adducts. In addition, we find that the preference for classical intercalation over a major groove position for the pyrenyl ring system in the [BP]-N 6-dA adducts stems from the advantage of burying the hydrophobic pyrenyl moiety within the helix rather than having it exposed in the large major groove.",
author = "Jian Tan and Geacintov, {Nicholas E.} and Suse Broyde",
year = "2000",
month = "4",
day = "5",
doi = "10.1021/ja993624h",
language = "English (US)",
volume = "122",
pages = "3021--3032",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "13",

}

TY - JOUR

T1 - Principles governing conformations in stereoisomeric adducts of Bay region benzo[a]pyrene diol epoxides to adenine in DNA

T2 - Steric and hydrophobic effects are dominant

AU - Tan, Jian

AU - Geacintov, Nicholas E.

AU - Broyde, Suse

PY - 2000/4/5

Y1 - 2000/4/5

N2 - The stereochemical properties of ligands that form covalent adducts with DNA have profound effects on their biochemical functions. Differing absolute configurations of substituents about chiral carbon atoms can lead to strikingly different conformations when such stereoisomeric compounds bind to DNA. The environmental chemical carcinogen, benzo[a]pyrene (BP), provides a remarkable example of such stereochemical effects. Metabolic activation of benzo[a]pyrene leads to a pair of enantiomers, (+)-(7R,8S,9S,10R)-7,8- dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its (-)- (7S,SR,9R,10S) mirror-image, known as (+)- and (-)-anti-BPDE. Both (+)- and (-)-anti-BPDE react with the amino group of adenine in DNA via trans epoxide opening, yielding a pair of stereochemically distinct trans-anti- benzo[a]pyrenyl adducts, whose possible role in chemical carcinogenesis is of great interest. High-resolution NMR solution studies (Schurter et al. Biochemistry 1995, 34, 1364-75; Yeh et al. Biochemistry 1995, 34, 13570-81; Zegar et al. Biochemistry 1996, 35, 621224; Schwartz et al., Biochemistry 1997, 36, 11069-76) have revealed that in the 10S (+)- and 10R (-)-trans-anti adducts, the BP is classically intercalated, residing on the 3'-side of the modified adenine in the (+)trans-anti adduct and on the 5'-side in the (-) stereoisomer. To elucidate the stereochemical principles underlying these conformational preferences, an extensive survey of the potential energy surface of each modified nucleoside was carried out, in which the energy of 373,248 structures for each adduct was computed using AMBER 5.0. Our results reveal near mirror image symmetries in the four pairs of low-energy structural domains of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts, which is rooted in the exact enantiomeric relationship of the BPDE precursors, and accounts for the opposite orientations observed in solution. Steric hindrance prevents an R isomer from assuming the orientation favored by the S isomer, and vice versa. The NMR solution structures of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts in DNA adopt conformations which are in the low-energy domains computed for the nucleoside adducts. In addition, we find that the preference for classical intercalation over a major groove position for the pyrenyl ring system in the [BP]-N 6-dA adducts stems from the advantage of burying the hydrophobic pyrenyl moiety within the helix rather than having it exposed in the large major groove.

AB - The stereochemical properties of ligands that form covalent adducts with DNA have profound effects on their biochemical functions. Differing absolute configurations of substituents about chiral carbon atoms can lead to strikingly different conformations when such stereoisomeric compounds bind to DNA. The environmental chemical carcinogen, benzo[a]pyrene (BP), provides a remarkable example of such stereochemical effects. Metabolic activation of benzo[a]pyrene leads to a pair of enantiomers, (+)-(7R,8S,9S,10R)-7,8- dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its (-)- (7S,SR,9R,10S) mirror-image, known as (+)- and (-)-anti-BPDE. Both (+)- and (-)-anti-BPDE react with the amino group of adenine in DNA via trans epoxide opening, yielding a pair of stereochemically distinct trans-anti- benzo[a]pyrenyl adducts, whose possible role in chemical carcinogenesis is of great interest. High-resolution NMR solution studies (Schurter et al. Biochemistry 1995, 34, 1364-75; Yeh et al. Biochemistry 1995, 34, 13570-81; Zegar et al. Biochemistry 1996, 35, 621224; Schwartz et al., Biochemistry 1997, 36, 11069-76) have revealed that in the 10S (+)- and 10R (-)-trans-anti adducts, the BP is classically intercalated, residing on the 3'-side of the modified adenine in the (+)trans-anti adduct and on the 5'-side in the (-) stereoisomer. To elucidate the stereochemical principles underlying these conformational preferences, an extensive survey of the potential energy surface of each modified nucleoside was carried out, in which the energy of 373,248 structures for each adduct was computed using AMBER 5.0. Our results reveal near mirror image symmetries in the four pairs of low-energy structural domains of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts, which is rooted in the exact enantiomeric relationship of the BPDE precursors, and accounts for the opposite orientations observed in solution. Steric hindrance prevents an R isomer from assuming the orientation favored by the S isomer, and vice versa. The NMR solution structures of 10S (+)- and 10R (-)-trans-anti-[BP]-N 6-dA adducts in DNA adopt conformations which are in the low-energy domains computed for the nucleoside adducts. In addition, we find that the preference for classical intercalation over a major groove position for the pyrenyl ring system in the [BP]-N 6-dA adducts stems from the advantage of burying the hydrophobic pyrenyl moiety within the helix rather than having it exposed in the large major groove.

UR - http://www.scopus.com/inward/record.url?scp=0034607407&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034607407&partnerID=8YFLogxK

U2 - 10.1021/ja993624h

DO - 10.1021/ja993624h

M3 - Article

AN - SCOPUS:0034607407

VL - 122

SP - 3021

EP - 3032

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 13

ER -