Solution conformation of the (-)-trans-anti-5-methylchrysene-dG adduct opposite dC in a DNA duplex: DNA bending associated with wedging of the methyl group of 5-methylchrysene to the 3'-side of the modification site

M. Cosman, R. Xu, B. E. Hingerty, S. Amin, R. G. Harvey, N. E. Geacintov, S. Broyde, D. J. Patel

Research output: Contribution to journalArticle

Abstract

This paper reports on NMR-molecular mechanics structural studies of the (-)-trans-anti-[MC]dG adduct positioned opposite dC in the sequence context of the d(C1-C2-A3-T4-C5-[MC]G6-C7-T8-A9-C10-C11).d(G12-G13-T14++ +-A15-G16-C17-G18- A19-T20-G21-G22) duplex [designated (-)-trans-anti-[MC]dG.dC 11-mer duplex]. This adduct is derived from the trans addition at C4 of (-)-anti-1(S),2(R)-dihydroxy-3(R),4(S)-epoxy-1,2,3,4-tetrahydro-5-met hylchrysen e [(-)-anti-5-MeCDE] to the N2 position of dG6 in this duplex sequence. The 5-methyl group is located adjacent to the MC(C4) binding site, with these groups juxtaposed in a sterically crowded bay region in the adduct duplex. The 5-methylchrysenyl and the nucleic acid exchangeable and nonexchangeable protons were assigned following analysis of two-dimensional NMR data sets in H2O and D2O buffer solution. The solution structure of the (-)-trans-anti-[MC]dG.dC 11-mer duplex has been determined by incorporating DNA-DNA and carcinogen-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. The results establish that the [MC]dG6.dC17 base pair and flanking dC5.dG18 and dC7.dG16 base pairs retain Watson-Crick alignments upon adduct formation. The aromatic chrysenyl ring is positioned in the minor groove of a right-handed B-DNA helix and stacks predominantly over the sugar of the dC17 residue across from it on the unmodified complementary strand. The chrysenyl ring points toward the 3'-end of the modified strand with its 5-methyl group inserting between the modified [MC]dG6.dC17 and dC7.dG16 base pairs. The adduct duplex bends by approximately 47 degrees as a result of the wedged insertion of the 5-methyl group from the minor groove face of the duplex. The solution structure of the (-)-trans-anti-[MC] dG.dC 11-mer duplex is compared with that of the corresponding (-)-trans-anti-[BP]dG.dC 11-mer [De los Santos et al. (1992) Biochemistry 31, 5245-5252] in which the [BP]dG adduct is derived from the binding of (-)-anti-BPDE [7(S),8(R)-dihydroxy-9(R),10(S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene] to the N2 position in the same DNA sequence context. Although the solution structures of the (-)-trans-anti-stereoisomers of 5-methylchrysenyl-dG and benzo[a]pyrenyl-dG adducts opposite dC exhibit many features in common with each other, the [MC]dG adduct which contains a bay region methyl group bends the DNA helix to a greater extent than in the corresponding [BP]dG adduct, which lacks a bay region methyl group.(ABSTRACT TRUNCATED AT 400 WORDS)
Original languageUndefined
Pages (from-to)6247-60
JournalBiochemistry
Volume34
Issue number18
StatePublished - 1995

Keywords

  • Chrysenes/*chemistry Computer Simulation DNA/*chemistry Deoxyguanosine/*chemistry Models, Molecular Molecular Conformation Molecular Structure Solutions

Cite this

@article{57df89626e4a457eb275ed9920cd2386,
title = "Solution conformation of the (-)-trans-anti-5-methylchrysene-dG adduct opposite dC in a DNA duplex: DNA bending associated with wedging of the methyl group of 5-methylchrysene to the 3'-side of the modification site",
abstract = "This paper reports on NMR-molecular mechanics structural studies of the (-)-trans-anti-[MC]dG adduct positioned opposite dC in the sequence context of the d(C1-C2-A3-T4-C5-[MC]G6-C7-T8-A9-C10-C11).d(G12-G13-T14++ +-A15-G16-C17-G18- A19-T20-G21-G22) duplex [designated (-)-trans-anti-[MC]dG.dC 11-mer duplex]. This adduct is derived from the trans addition at C4 of (-)-anti-1(S),2(R)-dihydroxy-3(R),4(S)-epoxy-1,2,3,4-tetrahydro-5-met hylchrysen e [(-)-anti-5-MeCDE] to the N2 position of dG6 in this duplex sequence. The 5-methyl group is located adjacent to the MC(C4) binding site, with these groups juxtaposed in a sterically crowded bay region in the adduct duplex. The 5-methylchrysenyl and the nucleic acid exchangeable and nonexchangeable protons were assigned following analysis of two-dimensional NMR data sets in H2O and D2O buffer solution. The solution structure of the (-)-trans-anti-[MC]dG.dC 11-mer duplex has been determined by incorporating DNA-DNA and carcinogen-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. The results establish that the [MC]dG6.dC17 base pair and flanking dC5.dG18 and dC7.dG16 base pairs retain Watson-Crick alignments upon adduct formation. The aromatic chrysenyl ring is positioned in the minor groove of a right-handed B-DNA helix and stacks predominantly over the sugar of the dC17 residue across from it on the unmodified complementary strand. The chrysenyl ring points toward the 3'-end of the modified strand with its 5-methyl group inserting between the modified [MC]dG6.dC17 and dC7.dG16 base pairs. The adduct duplex bends by approximately 47 degrees as a result of the wedged insertion of the 5-methyl group from the minor groove face of the duplex. The solution structure of the (-)-trans-anti-[MC] dG.dC 11-mer duplex is compared with that of the corresponding (-)-trans-anti-[BP]dG.dC 11-mer [De los Santos et al. (1992) Biochemistry 31, 5245-5252] in which the [BP]dG adduct is derived from the binding of (-)-anti-BPDE [7(S),8(R)-dihydroxy-9(R),10(S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene] to the N2 position in the same DNA sequence context. Although the solution structures of the (-)-trans-anti-stereoisomers of 5-methylchrysenyl-dG and benzo[a]pyrenyl-dG adducts opposite dC exhibit many features in common with each other, the [MC]dG adduct which contains a bay region methyl group bends the DNA helix to a greater extent than in the corresponding [BP]dG adduct, which lacks a bay region methyl group.(ABSTRACT TRUNCATED AT 400 WORDS)",
keywords = "Chrysenes/*chemistry Computer Simulation DNA/*chemistry Deoxyguanosine/*chemistry Models, Molecular Molecular Conformation Molecular Structure Solutions",
author = "M. Cosman and R. Xu and Hingerty, {B. E.} and S. Amin and Harvey, {R. G.} and Geacintov, {N. E.} and S. Broyde and Patel, {D. J.}",
note = "Cosman, M Xu, R Hingerty, B E Amin, S Harvey, R G Geacintov, N E Broyde, S Patel, D J CA-20851/CA/NCI NIH HHS/United States CA-28038/CA/NCI NIH HHS/United States CA-46533/CA/NCI NIH HHS/United States etc. Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. United states Biochemistry. 1995 May 9;34(18):6247-60.",
year = "1995",
language = "Undefined",
volume = "34",
pages = "6247--60",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "18",

}

TY - JOUR

T1 - Solution conformation of the (-)-trans-anti-5-methylchrysene-dG adduct opposite dC in a DNA duplex: DNA bending associated with wedging of the methyl group of 5-methylchrysene to the 3'-side of the modification site

AU - Cosman, M.

AU - Xu, R.

AU - Hingerty, B. E.

AU - Amin, S.

AU - Harvey, R. G.

AU - Geacintov, N. E.

AU - Broyde, S.

AU - Patel, D. J.

N1 - Cosman, M Xu, R Hingerty, B E Amin, S Harvey, R G Geacintov, N E Broyde, S Patel, D J CA-20851/CA/NCI NIH HHS/United States CA-28038/CA/NCI NIH HHS/United States CA-46533/CA/NCI NIH HHS/United States etc. Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. United states Biochemistry. 1995 May 9;34(18):6247-60.

PY - 1995

Y1 - 1995

N2 - This paper reports on NMR-molecular mechanics structural studies of the (-)-trans-anti-[MC]dG adduct positioned opposite dC in the sequence context of the d(C1-C2-A3-T4-C5-[MC]G6-C7-T8-A9-C10-C11).d(G12-G13-T14++ +-A15-G16-C17-G18- A19-T20-G21-G22) duplex [designated (-)-trans-anti-[MC]dG.dC 11-mer duplex]. This adduct is derived from the trans addition at C4 of (-)-anti-1(S),2(R)-dihydroxy-3(R),4(S)-epoxy-1,2,3,4-tetrahydro-5-met hylchrysen e [(-)-anti-5-MeCDE] to the N2 position of dG6 in this duplex sequence. The 5-methyl group is located adjacent to the MC(C4) binding site, with these groups juxtaposed in a sterically crowded bay region in the adduct duplex. The 5-methylchrysenyl and the nucleic acid exchangeable and nonexchangeable protons were assigned following analysis of two-dimensional NMR data sets in H2O and D2O buffer solution. The solution structure of the (-)-trans-anti-[MC]dG.dC 11-mer duplex has been determined by incorporating DNA-DNA and carcinogen-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. The results establish that the [MC]dG6.dC17 base pair and flanking dC5.dG18 and dC7.dG16 base pairs retain Watson-Crick alignments upon adduct formation. The aromatic chrysenyl ring is positioned in the minor groove of a right-handed B-DNA helix and stacks predominantly over the sugar of the dC17 residue across from it on the unmodified complementary strand. The chrysenyl ring points toward the 3'-end of the modified strand with its 5-methyl group inserting between the modified [MC]dG6.dC17 and dC7.dG16 base pairs. The adduct duplex bends by approximately 47 degrees as a result of the wedged insertion of the 5-methyl group from the minor groove face of the duplex. The solution structure of the (-)-trans-anti-[MC] dG.dC 11-mer duplex is compared with that of the corresponding (-)-trans-anti-[BP]dG.dC 11-mer [De los Santos et al. (1992) Biochemistry 31, 5245-5252] in which the [BP]dG adduct is derived from the binding of (-)-anti-BPDE [7(S),8(R)-dihydroxy-9(R),10(S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene] to the N2 position in the same DNA sequence context. Although the solution structures of the (-)-trans-anti-stereoisomers of 5-methylchrysenyl-dG and benzo[a]pyrenyl-dG adducts opposite dC exhibit many features in common with each other, the [MC]dG adduct which contains a bay region methyl group bends the DNA helix to a greater extent than in the corresponding [BP]dG adduct, which lacks a bay region methyl group.(ABSTRACT TRUNCATED AT 400 WORDS)

AB - This paper reports on NMR-molecular mechanics structural studies of the (-)-trans-anti-[MC]dG adduct positioned opposite dC in the sequence context of the d(C1-C2-A3-T4-C5-[MC]G6-C7-T8-A9-C10-C11).d(G12-G13-T14++ +-A15-G16-C17-G18- A19-T20-G21-G22) duplex [designated (-)-trans-anti-[MC]dG.dC 11-mer duplex]. This adduct is derived from the trans addition at C4 of (-)-anti-1(S),2(R)-dihydroxy-3(R),4(S)-epoxy-1,2,3,4-tetrahydro-5-met hylchrysen e [(-)-anti-5-MeCDE] to the N2 position of dG6 in this duplex sequence. The 5-methyl group is located adjacent to the MC(C4) binding site, with these groups juxtaposed in a sterically crowded bay region in the adduct duplex. The 5-methylchrysenyl and the nucleic acid exchangeable and nonexchangeable protons were assigned following analysis of two-dimensional NMR data sets in H2O and D2O buffer solution. The solution structure of the (-)-trans-anti-[MC]dG.dC 11-mer duplex has been determined by incorporating DNA-DNA and carcinogen-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. The results establish that the [MC]dG6.dC17 base pair and flanking dC5.dG18 and dC7.dG16 base pairs retain Watson-Crick alignments upon adduct formation. The aromatic chrysenyl ring is positioned in the minor groove of a right-handed B-DNA helix and stacks predominantly over the sugar of the dC17 residue across from it on the unmodified complementary strand. The chrysenyl ring points toward the 3'-end of the modified strand with its 5-methyl group inserting between the modified [MC]dG6.dC17 and dC7.dG16 base pairs. The adduct duplex bends by approximately 47 degrees as a result of the wedged insertion of the 5-methyl group from the minor groove face of the duplex. The solution structure of the (-)-trans-anti-[MC] dG.dC 11-mer duplex is compared with that of the corresponding (-)-trans-anti-[BP]dG.dC 11-mer [De los Santos et al. (1992) Biochemistry 31, 5245-5252] in which the [BP]dG adduct is derived from the binding of (-)-anti-BPDE [7(S),8(R)-dihydroxy-9(R),10(S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene] to the N2 position in the same DNA sequence context. Although the solution structures of the (-)-trans-anti-stereoisomers of 5-methylchrysenyl-dG and benzo[a]pyrenyl-dG adducts opposite dC exhibit many features in common with each other, the [MC]dG adduct which contains a bay region methyl group bends the DNA helix to a greater extent than in the corresponding [BP]dG adduct, which lacks a bay region methyl group.(ABSTRACT TRUNCATED AT 400 WORDS)

KW - Chrysenes/chemistry Computer Simulation DNA/chemistry Deoxyguanosine/chemistry Models, Molecular Molecular Conformation Molecular Structure Solutions

M3 - Article

VL - 34

SP - 6247

EP - 6260

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 18

ER -