Intercalative conformations of the 14R(+)- and 14S(-)- trans-anti-DB[a,l]P- N6-dA adducts

Molecular modeling and MD simulations

Yuqin Cai, Shuang Ding, Nicholas E. Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

Among the polycyclic aromatic hydrocarbon class of chemical carcinogens, dibenzo[a,l]pyrene (DB[a,l]P) is the most potent tumorigen that has been identified to date. Structurally, it is bulky with six aromatic rings, and it contains the nonplanar fjord-region. The conformational properties of DB[a,l]P-derived DNA adducts responsible for its extraordinary carcinogenicity are hence of great interest. We have carried out molecular modeling and MD simulations for the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N6-dA adducts derived from the reactions of the DB[a,l]P diol epoxides with adenine in double-stranded DNA. The structures are based on the classically intercalated NMR solution structures of the analogous fjord-region benzo[c]phenanthrene- derived-N6-dA adducts. One objective was to gain insight on the impact of the more bulky DB[a,l]P ring system on the structural characteristics of the intercalative adduct conformations. A further objective was to elucidate the effect of the flexible twist associated with the sterically hindered aromatic ring in the fjord-region on the intercalated conformations, for comparison with the intercalated but planar bay-region benzo[a]pyrene-derived- N6-dA adducts. For the DB[a,l]P-N6-dA adducts, our results show that the 14R (+)-adduct is more favorably intercalated on the 5′-side of the modified adenine than the stereoisomeric 14S (-)-adduct, intercalated on its 3′-side. The 14R (+)-adduct manifests better van der Waals stacking interactions with flanking base pairs, less perturbed Watson-Crick hydrogen bonding, less local groove enlargement, less unwinding, and a lower solvent exposure than the 14S (-)-adduct. These structural findings are consistent with observed thermodynamic melting data, UV absorption properties, and fluorescence quenching studies. By contrast, the NMR solution structures for the analogous but less bulky B[c]Ph-derived adducts reveal no such stereoisomeric effect, while the planar bay-region benzo[a]pyrene-derived- N6-dA adducts do. Differences in nucleotide excision repair susceptibilities of the fjord and bay region adducts stem from distinctions in their intercalative conformations, produced by the intrinsic topological variations in their polycyclic aromatic ring systems.

Original languageEnglish (US)
Pages (from-to)522-531
Number of pages10
JournalChemical Research in Toxicology
Volume24
Issue number4
DOIs
StatePublished - Apr 18 2011

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Estuaries
Molecular modeling
Conformations
Benzo(a)pyrene
Adenine
Nuclear magnetic resonance
DNA Adducts
Polycyclic Aromatic Hydrocarbons
Epoxy Compounds
Carcinogens
Quenching
Hydrogen bonds
Melting
Repair
Hydrogen Bonding
Nucleotides
Fluorescence
Thermodynamics
Base Pairing
DNA Repair

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{2d565067efc04f73a208c8e547e1e4e8,
title = "Intercalative conformations of the 14R(+)- and 14S(-)- trans-anti-DB[a,l]P- N6-dA adducts: Molecular modeling and MD simulations",
abstract = "Among the polycyclic aromatic hydrocarbon class of chemical carcinogens, dibenzo[a,l]pyrene (DB[a,l]P) is the most potent tumorigen that has been identified to date. Structurally, it is bulky with six aromatic rings, and it contains the nonplanar fjord-region. The conformational properties of DB[a,l]P-derived DNA adducts responsible for its extraordinary carcinogenicity are hence of great interest. We have carried out molecular modeling and MD simulations for the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N6-dA adducts derived from the reactions of the DB[a,l]P diol epoxides with adenine in double-stranded DNA. The structures are based on the classically intercalated NMR solution structures of the analogous fjord-region benzo[c]phenanthrene- derived-N6-dA adducts. One objective was to gain insight on the impact of the more bulky DB[a,l]P ring system on the structural characteristics of the intercalative adduct conformations. A further objective was to elucidate the effect of the flexible twist associated with the sterically hindered aromatic ring in the fjord-region on the intercalated conformations, for comparison with the intercalated but planar bay-region benzo[a]pyrene-derived- N6-dA adducts. For the DB[a,l]P-N6-dA adducts, our results show that the 14R (+)-adduct is more favorably intercalated on the 5′-side of the modified adenine than the stereoisomeric 14S (-)-adduct, intercalated on its 3′-side. The 14R (+)-adduct manifests better van der Waals stacking interactions with flanking base pairs, less perturbed Watson-Crick hydrogen bonding, less local groove enlargement, less unwinding, and a lower solvent exposure than the 14S (-)-adduct. These structural findings are consistent with observed thermodynamic melting data, UV absorption properties, and fluorescence quenching studies. By contrast, the NMR solution structures for the analogous but less bulky B[c]Ph-derived adducts reveal no such stereoisomeric effect, while the planar bay-region benzo[a]pyrene-derived- N6-dA adducts do. Differences in nucleotide excision repair susceptibilities of the fjord and bay region adducts stem from distinctions in their intercalative conformations, produced by the intrinsic topological variations in their polycyclic aromatic ring systems.",
author = "Yuqin Cai and Shuang Ding and Geacintov, {Nicholas E.} and Suse Broyde",
year = "2011",
month = "4",
day = "18",
doi = "10.1021/tx1004002",
language = "English (US)",
volume = "24",
pages = "522--531",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - Intercalative conformations of the 14R(+)- and 14S(-)- trans-anti-DB[a,l]P- N6-dA adducts

T2 - Molecular modeling and MD simulations

AU - Cai, Yuqin

AU - Ding, Shuang

AU - Geacintov, Nicholas E.

AU - Broyde, Suse

PY - 2011/4/18

Y1 - 2011/4/18

N2 - Among the polycyclic aromatic hydrocarbon class of chemical carcinogens, dibenzo[a,l]pyrene (DB[a,l]P) is the most potent tumorigen that has been identified to date. Structurally, it is bulky with six aromatic rings, and it contains the nonplanar fjord-region. The conformational properties of DB[a,l]P-derived DNA adducts responsible for its extraordinary carcinogenicity are hence of great interest. We have carried out molecular modeling and MD simulations for the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N6-dA adducts derived from the reactions of the DB[a,l]P diol epoxides with adenine in double-stranded DNA. The structures are based on the classically intercalated NMR solution structures of the analogous fjord-region benzo[c]phenanthrene- derived-N6-dA adducts. One objective was to gain insight on the impact of the more bulky DB[a,l]P ring system on the structural characteristics of the intercalative adduct conformations. A further objective was to elucidate the effect of the flexible twist associated with the sterically hindered aromatic ring in the fjord-region on the intercalated conformations, for comparison with the intercalated but planar bay-region benzo[a]pyrene-derived- N6-dA adducts. For the DB[a,l]P-N6-dA adducts, our results show that the 14R (+)-adduct is more favorably intercalated on the 5′-side of the modified adenine than the stereoisomeric 14S (-)-adduct, intercalated on its 3′-side. The 14R (+)-adduct manifests better van der Waals stacking interactions with flanking base pairs, less perturbed Watson-Crick hydrogen bonding, less local groove enlargement, less unwinding, and a lower solvent exposure than the 14S (-)-adduct. These structural findings are consistent with observed thermodynamic melting data, UV absorption properties, and fluorescence quenching studies. By contrast, the NMR solution structures for the analogous but less bulky B[c]Ph-derived adducts reveal no such stereoisomeric effect, while the planar bay-region benzo[a]pyrene-derived- N6-dA adducts do. Differences in nucleotide excision repair susceptibilities of the fjord and bay region adducts stem from distinctions in their intercalative conformations, produced by the intrinsic topological variations in their polycyclic aromatic ring systems.

AB - Among the polycyclic aromatic hydrocarbon class of chemical carcinogens, dibenzo[a,l]pyrene (DB[a,l]P) is the most potent tumorigen that has been identified to date. Structurally, it is bulky with six aromatic rings, and it contains the nonplanar fjord-region. The conformational properties of DB[a,l]P-derived DNA adducts responsible for its extraordinary carcinogenicity are hence of great interest. We have carried out molecular modeling and MD simulations for the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N6-dA adducts derived from the reactions of the DB[a,l]P diol epoxides with adenine in double-stranded DNA. The structures are based on the classically intercalated NMR solution structures of the analogous fjord-region benzo[c]phenanthrene- derived-N6-dA adducts. One objective was to gain insight on the impact of the more bulky DB[a,l]P ring system on the structural characteristics of the intercalative adduct conformations. A further objective was to elucidate the effect of the flexible twist associated with the sterically hindered aromatic ring in the fjord-region on the intercalated conformations, for comparison with the intercalated but planar bay-region benzo[a]pyrene-derived- N6-dA adducts. For the DB[a,l]P-N6-dA adducts, our results show that the 14R (+)-adduct is more favorably intercalated on the 5′-side of the modified adenine than the stereoisomeric 14S (-)-adduct, intercalated on its 3′-side. The 14R (+)-adduct manifests better van der Waals stacking interactions with flanking base pairs, less perturbed Watson-Crick hydrogen bonding, less local groove enlargement, less unwinding, and a lower solvent exposure than the 14S (-)-adduct. These structural findings are consistent with observed thermodynamic melting data, UV absorption properties, and fluorescence quenching studies. By contrast, the NMR solution structures for the analogous but less bulky B[c]Ph-derived adducts reveal no such stereoisomeric effect, while the planar bay-region benzo[a]pyrene-derived- N6-dA adducts do. Differences in nucleotide excision repair susceptibilities of the fjord and bay region adducts stem from distinctions in their intercalative conformations, produced by the intrinsic topological variations in their polycyclic aromatic ring systems.

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U2 - 10.1021/tx1004002

DO - 10.1021/tx1004002

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