Structural alignment of the (+)-trans-anti-benzo[a]pyrene-dG adduct positioned opposite dC at a DNA template-primer junction

Binbin Feng, Andrey Gorin, Brian E. Hingerty, Nicholas E. Geacintov, Suse Broyde, Dinshaw J. Patel

Research output: Contribution to journalArticle

Abstract

This study reports on the solution conformation of the covalent (+)- trans-anti-[BP]dG adduct (derived from the binding of the highly mutagenic and tumorigenic (+)-anti-benzo[a]pyrene diol epoxide to the N2 of deoxyguanosine) positioned opposite dC at a junctional site in the d(A1-A2- C3-[BP]G4-C5T6-A7-CS-C9-A10-T11-C12-C13)·d(G14-G15-A16-T17-G18-G19-T20-A21- G22-C23) 13/10-met DNA sequence. The 13-mer represents the template strand containing the junction [BP]dG4 lesion while the complementary 10-mer models a primer strand which extends upto and is complementary to the modified dG4 residue. The solution conformation has been determined by initially incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOESY spectra as restraints in molecular mechanics computations in torsion angle space and subsequently through restrained molecular dynamics calculations based on a NeE distance and intensity refinement protocol. The duplex segment retains a minimally perturbed B-DNA conformation with all base pairs, including the junctional [BP]dG4·dC23 pair, in Watson-Crick hydrogen-bonded alignments. The pyrenyl ring is not stacked over the adjacent dC5·dG22 base pair but is positioned on the minor groove-side of the [BP]dG moiety and directed toward the 5'-end of the template strand. The pyrenyl ring stacks over the base of the non- adjacent dA2 residue in one direction and the sugar ring of dC23 in the other direction. The solution structure of the (+)-trans-anti-[BP]dG adduct opposite dC in the 13/10-met in which the modified deoxyguanosine adopts an anti glycosidic torsion angle (this study) is in striking contrast to the structure of the same (+)-trans-anti-[BP]dG moiety in a 13/9-mer of the same sequence but without the dC23 residue positioned opposite the adduct site [Cosman, M., et al. (1995) Biochemistry 34, 15334-15350]. For the latter case, the aromatic portion of the BP residue stacks over the adjacent dC5·dG22 base pair, the modified deoxyguanosine adopts a syn glycosidic torsion angle and is displaced toward the major groove direction. Insights into the factors that affect the sequence and context dependent conformations of stereoisomeric [BP]dG lesions have emerged following comparison of these two structures with the minor groove conformations of the same (+)-trans- anti-[BP]dG lesion in the fully complementary 11-mer duplex [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] and in the base displaced-intercalative conformation of the 11/10-mer deletion duplex containing a -1 deletion site opposite the lesion [Cosman, M., et al. (1994) Biochemistry 33, 11507-11517]. The contributing factors where applicable include Watson-Crick base pairing at the site of the lesion, positioning of the carcinogen within the floor of the minor groove, and the tendency of the bulky hydrophobic aromatic BP residue to assume stacked or intercalative conformations.

Original languageEnglish (US)
Pages (from-to)13769-13779
Number of pages11
JournalBiochemistry
Volume36
Issue number45
DOIs
StatePublished - Nov 11 1997

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DNA Primers
Benzo(a)pyrene
Base Pairing
Deoxyguanosine
Conformations
DNA
Biochemistry
Protons
Torsional stress
Molecular Computers
B-Form DNA
Epoxy Compounds
antineoplaston A10
Molecular Dynamics Simulation
Mechanics
varespladib methyl
Carcinogens
Hydrogen
Molecular mechanics
DNA sequences

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structural alignment of the (+)-trans-anti-benzo[a]pyrene-dG adduct positioned opposite dC at a DNA template-primer junction. / Feng, Binbin; Gorin, Andrey; Hingerty, Brian E.; Geacintov, Nicholas E.; Broyde, Suse; Patel, Dinshaw J.

In: Biochemistry, Vol. 36, No. 45, 11.11.1997, p. 13769-13779.

Research output: Contribution to journalArticle

Feng, Binbin ; Gorin, Andrey ; Hingerty, Brian E. ; Geacintov, Nicholas E. ; Broyde, Suse ; Patel, Dinshaw J. / Structural alignment of the (+)-trans-anti-benzo[a]pyrene-dG adduct positioned opposite dC at a DNA template-primer junction. In: Biochemistry. 1997 ; Vol. 36, No. 45. pp. 13769-13779.
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abstract = "This study reports on the solution conformation of the covalent (+)- trans-anti-[BP]dG adduct (derived from the binding of the highly mutagenic and tumorigenic (+)-anti-benzo[a]pyrene diol epoxide to the N2 of deoxyguanosine) positioned opposite dC at a junctional site in the d(A1-A2- C3-[BP]G4-C5T6-A7-CS-C9-A10-T11-C12-C13)·d(G14-G15-A16-T17-G18-G19-T20-A21- G22-C23) 13/10-met DNA sequence. The 13-mer represents the template strand containing the junction [BP]dG4 lesion while the complementary 10-mer models a primer strand which extends upto and is complementary to the modified dG4 residue. The solution conformation has been determined by initially incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOESY spectra as restraints in molecular mechanics computations in torsion angle space and subsequently through restrained molecular dynamics calculations based on a NeE distance and intensity refinement protocol. The duplex segment retains a minimally perturbed B-DNA conformation with all base pairs, including the junctional [BP]dG4·dC23 pair, in Watson-Crick hydrogen-bonded alignments. The pyrenyl ring is not stacked over the adjacent dC5·dG22 base pair but is positioned on the minor groove-side of the [BP]dG moiety and directed toward the 5'-end of the template strand. The pyrenyl ring stacks over the base of the non- adjacent dA2 residue in one direction and the sugar ring of dC23 in the other direction. The solution structure of the (+)-trans-anti-[BP]dG adduct opposite dC in the 13/10-met in which the modified deoxyguanosine adopts an anti glycosidic torsion angle (this study) is in striking contrast to the structure of the same (+)-trans-anti-[BP]dG moiety in a 13/9-mer of the same sequence but without the dC23 residue positioned opposite the adduct site [Cosman, M., et al. (1995) Biochemistry 34, 15334-15350]. For the latter case, the aromatic portion of the BP residue stacks over the adjacent dC5·dG22 base pair, the modified deoxyguanosine adopts a syn glycosidic torsion angle and is displaced toward the major groove direction. Insights into the factors that affect the sequence and context dependent conformations of stereoisomeric [BP]dG lesions have emerged following comparison of these two structures with the minor groove conformations of the same (+)-trans- anti-[BP]dG lesion in the fully complementary 11-mer duplex [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] and in the base displaced-intercalative conformation of the 11/10-mer deletion duplex containing a -1 deletion site opposite the lesion [Cosman, M., et al. (1994) Biochemistry 33, 11507-11517]. The contributing factors where applicable include Watson-Crick base pairing at the site of the lesion, positioning of the carcinogen within the floor of the minor groove, and the tendency of the bulky hydrophobic aromatic BP residue to assume stacked or intercalative conformations.",
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T1 - Structural alignment of the (+)-trans-anti-benzo[a]pyrene-dG adduct positioned opposite dC at a DNA template-primer junction

AU - Feng, Binbin

AU - Gorin, Andrey

AU - Hingerty, Brian E.

AU - Geacintov, Nicholas E.

AU - Broyde, Suse

AU - Patel, Dinshaw J.

PY - 1997/11/11

Y1 - 1997/11/11

N2 - This study reports on the solution conformation of the covalent (+)- trans-anti-[BP]dG adduct (derived from the binding of the highly mutagenic and tumorigenic (+)-anti-benzo[a]pyrene diol epoxide to the N2 of deoxyguanosine) positioned opposite dC at a junctional site in the d(A1-A2- C3-[BP]G4-C5T6-A7-CS-C9-A10-T11-C12-C13)·d(G14-G15-A16-T17-G18-G19-T20-A21- G22-C23) 13/10-met DNA sequence. The 13-mer represents the template strand containing the junction [BP]dG4 lesion while the complementary 10-mer models a primer strand which extends upto and is complementary to the modified dG4 residue. The solution conformation has been determined by initially incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOESY spectra as restraints in molecular mechanics computations in torsion angle space and subsequently through restrained molecular dynamics calculations based on a NeE distance and intensity refinement protocol. The duplex segment retains a minimally perturbed B-DNA conformation with all base pairs, including the junctional [BP]dG4·dC23 pair, in Watson-Crick hydrogen-bonded alignments. The pyrenyl ring is not stacked over the adjacent dC5·dG22 base pair but is positioned on the minor groove-side of the [BP]dG moiety and directed toward the 5'-end of the template strand. The pyrenyl ring stacks over the base of the non- adjacent dA2 residue in one direction and the sugar ring of dC23 in the other direction. The solution structure of the (+)-trans-anti-[BP]dG adduct opposite dC in the 13/10-met in which the modified deoxyguanosine adopts an anti glycosidic torsion angle (this study) is in striking contrast to the structure of the same (+)-trans-anti-[BP]dG moiety in a 13/9-mer of the same sequence but without the dC23 residue positioned opposite the adduct site [Cosman, M., et al. (1995) Biochemistry 34, 15334-15350]. For the latter case, the aromatic portion of the BP residue stacks over the adjacent dC5·dG22 base pair, the modified deoxyguanosine adopts a syn glycosidic torsion angle and is displaced toward the major groove direction. Insights into the factors that affect the sequence and context dependent conformations of stereoisomeric [BP]dG lesions have emerged following comparison of these two structures with the minor groove conformations of the same (+)-trans- anti-[BP]dG lesion in the fully complementary 11-mer duplex [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] and in the base displaced-intercalative conformation of the 11/10-mer deletion duplex containing a -1 deletion site opposite the lesion [Cosman, M., et al. (1994) Biochemistry 33, 11507-11517]. The contributing factors where applicable include Watson-Crick base pairing at the site of the lesion, positioning of the carcinogen within the floor of the minor groove, and the tendency of the bulky hydrophobic aromatic BP residue to assume stacked or intercalative conformations.

AB - This study reports on the solution conformation of the covalent (+)- trans-anti-[BP]dG adduct (derived from the binding of the highly mutagenic and tumorigenic (+)-anti-benzo[a]pyrene diol epoxide to the N2 of deoxyguanosine) positioned opposite dC at a junctional site in the d(A1-A2- C3-[BP]G4-C5T6-A7-CS-C9-A10-T11-C12-C13)·d(G14-G15-A16-T17-G18-G19-T20-A21- G22-C23) 13/10-met DNA sequence. The 13-mer represents the template strand containing the junction [BP]dG4 lesion while the complementary 10-mer models a primer strand which extends upto and is complementary to the modified dG4 residue. The solution conformation has been determined by initially incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOESY spectra as restraints in molecular mechanics computations in torsion angle space and subsequently through restrained molecular dynamics calculations based on a NeE distance and intensity refinement protocol. The duplex segment retains a minimally perturbed B-DNA conformation with all base pairs, including the junctional [BP]dG4·dC23 pair, in Watson-Crick hydrogen-bonded alignments. The pyrenyl ring is not stacked over the adjacent dC5·dG22 base pair but is positioned on the minor groove-side of the [BP]dG moiety and directed toward the 5'-end of the template strand. The pyrenyl ring stacks over the base of the non- adjacent dA2 residue in one direction and the sugar ring of dC23 in the other direction. The solution structure of the (+)-trans-anti-[BP]dG adduct opposite dC in the 13/10-met in which the modified deoxyguanosine adopts an anti glycosidic torsion angle (this study) is in striking contrast to the structure of the same (+)-trans-anti-[BP]dG moiety in a 13/9-mer of the same sequence but without the dC23 residue positioned opposite the adduct site [Cosman, M., et al. (1995) Biochemistry 34, 15334-15350]. For the latter case, the aromatic portion of the BP residue stacks over the adjacent dC5·dG22 base pair, the modified deoxyguanosine adopts a syn glycosidic torsion angle and is displaced toward the major groove direction. Insights into the factors that affect the sequence and context dependent conformations of stereoisomeric [BP]dG lesions have emerged following comparison of these two structures with the minor groove conformations of the same (+)-trans- anti-[BP]dG lesion in the fully complementary 11-mer duplex [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] and in the base displaced-intercalative conformation of the 11/10-mer deletion duplex containing a -1 deletion site opposite the lesion [Cosman, M., et al. (1994) Biochemistry 33, 11507-11517]. The contributing factors where applicable include Watson-Crick base pairing at the site of the lesion, positioning of the carcinogen within the floor of the minor groove, and the tendency of the bulky hydrophobic aromatic BP residue to assume stacked or intercalative conformations.

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