Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes

Energetic and structural relationships to nucleotide excision repair susceptibility

Yuqin Cai, Han Zheng, Shuang Ding, Konstantin Kropachev, Adam G. Schwaid, Yijin Tang, Hong Mu, Shenglong Wang, Nicholas E. Geacintov, Yingkai Zhang, Suse Broyde

Research output: Contribution to journalArticle

Abstract

The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B (Min, J. H. and Pavletich, N. P. (2007) Nature449, 570-575) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This suggests the hypothesis that the flipping of this partner base must overcome a free energy barrier, which constitutes one element contributing to changes in the thermodynamic properties induced by the DNA damage and sensed by the recognition protein. We explored this hypothesis by computing complete flipping free energy profiles for two lesions derived from the procarcinogenic polycyclic aromatic hydrocarbons (PAHs), dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P), R-trans-anti-DB[a,l]P-N6-dA (R-DB[a,l]P-dA) and R-trans-anti-B[a]P-N6-dA (R-B[a]P-dA), and the corresponding unmodified duplex. The DB[a,l]P and B[a]P adducts differ in number and organization of their aromatic rings. We integrate these results with prior profiles for the R-trans-anti-DB[a,l]P-dG adduct (Zheng, H. et al. (2010) Chem. Res. Toxicol.23, 1868-1870). All adopt conformational themes involving intercalation of the PAH aromatic ring system into the DNA duplex; however, R-DB[a,l]P-dA and R-B[a]P-dA intercalate from the major groove, while R-DB[a,l]P-dG intercalates from the minor groove. These structural differences produce different computed van der Waals stacking interaction energies between the flipping partner base with the lesion aromatic ring system and adjacent bases; we find that the better the stacking, the higher the relative flipping free energy barrier and hence lower flipping probability. The better relative NER susceptibilities correlate with greater ease of flipping in these three differently intercalated lesions. In addition to partner base flipping, the Rad4/Rad23 crystal structure shows that a protein-β-hairpin, BHD3, intrudes from the major groove side between the DNA strands at the lesion site. We present a molecular modeling study for the R-DB[a,l]P-dG lesion in Rad4/Rad23 showing BHD3 β-hairpin intrusion with lesion eviction, and we hypothesize that lesion steric effects play a role in the recognition of intercalated adducts.

Original languageEnglish (US)
Pages (from-to)1115-1125
Number of pages11
JournalChemical Research in Toxicology
Volume26
Issue number7
DOIs
StatePublished - Jul 15 2013

Fingerprint

Benzo(a)pyrene
Polycyclic Aromatic Hydrocarbons
DNA Repair
Free energy
Repair
Nucleotides
DNA
Energy barriers
Crystal structure
Proteins
Molecular modeling
Intercalation
Thermodynamics
Yeast
DNA Damage
Thermodynamic properties
Yeasts
Amino Acids

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes : Energetic and structural relationships to nucleotide excision repair susceptibility. / Cai, Yuqin; Zheng, Han; Ding, Shuang; Kropachev, Konstantin; Schwaid, Adam G.; Tang, Yijin; Mu, Hong; Wang, Shenglong; Geacintov, Nicholas E.; Zhang, Yingkai; Broyde, Suse.

In: Chemical Research in Toxicology, Vol. 26, No. 7, 15.07.2013, p. 1115-1125.

Research output: Contribution to journalArticle

@article{c7fe96c713784d0baf8b80bfe5d24948,
title = "Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes: Energetic and structural relationships to nucleotide excision repair susceptibility",
abstract = "The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B (Min, J. H. and Pavletich, N. P. (2007) Nature449, 570-575) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This suggests the hypothesis that the flipping of this partner base must overcome a free energy barrier, which constitutes one element contributing to changes in the thermodynamic properties induced by the DNA damage and sensed by the recognition protein. We explored this hypothesis by computing complete flipping free energy profiles for two lesions derived from the procarcinogenic polycyclic aromatic hydrocarbons (PAHs), dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P), R-trans-anti-DB[a,l]P-N6-dA (R-DB[a,l]P-dA) and R-trans-anti-B[a]P-N6-dA (R-B[a]P-dA), and the corresponding unmodified duplex. The DB[a,l]P and B[a]P adducts differ in number and organization of their aromatic rings. We integrate these results with prior profiles for the R-trans-anti-DB[a,l]P-dG adduct (Zheng, H. et al. (2010) Chem. Res. Toxicol.23, 1868-1870). All adopt conformational themes involving intercalation of the PAH aromatic ring system into the DNA duplex; however, R-DB[a,l]P-dA and R-B[a]P-dA intercalate from the major groove, while R-DB[a,l]P-dG intercalates from the minor groove. These structural differences produce different computed van der Waals stacking interaction energies between the flipping partner base with the lesion aromatic ring system and adjacent bases; we find that the better the stacking, the higher the relative flipping free energy barrier and hence lower flipping probability. The better relative NER susceptibilities correlate with greater ease of flipping in these three differently intercalated lesions. In addition to partner base flipping, the Rad4/Rad23 crystal structure shows that a protein-β-hairpin, BHD3, intrudes from the major groove side between the DNA strands at the lesion site. We present a molecular modeling study for the R-DB[a,l]P-dG lesion in Rad4/Rad23 showing BHD3 β-hairpin intrusion with lesion eviction, and we hypothesize that lesion steric effects play a role in the recognition of intercalated adducts.",
author = "Yuqin Cai and Han Zheng and Shuang Ding and Konstantin Kropachev and Schwaid, {Adam G.} and Yijin Tang and Hong Mu and Shenglong Wang and Geacintov, {Nicholas E.} and Yingkai Zhang and Suse Broyde",
year = "2013",
month = "7",
day = "15",
doi = "10.1021/tx400156a",
language = "English (US)",
volume = "26",
pages = "1115--1125",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes

T2 - Energetic and structural relationships to nucleotide excision repair susceptibility

AU - Cai, Yuqin

AU - Zheng, Han

AU - Ding, Shuang

AU - Kropachev, Konstantin

AU - Schwaid, Adam G.

AU - Tang, Yijin

AU - Mu, Hong

AU - Wang, Shenglong

AU - Geacintov, Nicholas E.

AU - Zhang, Yingkai

AU - Broyde, Suse

PY - 2013/7/15

Y1 - 2013/7/15

N2 - The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B (Min, J. H. and Pavletich, N. P. (2007) Nature449, 570-575) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This suggests the hypothesis that the flipping of this partner base must overcome a free energy barrier, which constitutes one element contributing to changes in the thermodynamic properties induced by the DNA damage and sensed by the recognition protein. We explored this hypothesis by computing complete flipping free energy profiles for two lesions derived from the procarcinogenic polycyclic aromatic hydrocarbons (PAHs), dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P), R-trans-anti-DB[a,l]P-N6-dA (R-DB[a,l]P-dA) and R-trans-anti-B[a]P-N6-dA (R-B[a]P-dA), and the corresponding unmodified duplex. The DB[a,l]P and B[a]P adducts differ in number and organization of their aromatic rings. We integrate these results with prior profiles for the R-trans-anti-DB[a,l]P-dG adduct (Zheng, H. et al. (2010) Chem. Res. Toxicol.23, 1868-1870). All adopt conformational themes involving intercalation of the PAH aromatic ring system into the DNA duplex; however, R-DB[a,l]P-dA and R-B[a]P-dA intercalate from the major groove, while R-DB[a,l]P-dG intercalates from the minor groove. These structural differences produce different computed van der Waals stacking interaction energies between the flipping partner base with the lesion aromatic ring system and adjacent bases; we find that the better the stacking, the higher the relative flipping free energy barrier and hence lower flipping probability. The better relative NER susceptibilities correlate with greater ease of flipping in these three differently intercalated lesions. In addition to partner base flipping, the Rad4/Rad23 crystal structure shows that a protein-β-hairpin, BHD3, intrudes from the major groove side between the DNA strands at the lesion site. We present a molecular modeling study for the R-DB[a,l]P-dG lesion in Rad4/Rad23 showing BHD3 β-hairpin intrusion with lesion eviction, and we hypothesize that lesion steric effects play a role in the recognition of intercalated adducts.

AB - The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B (Min, J. H. and Pavletich, N. P. (2007) Nature449, 570-575) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This suggests the hypothesis that the flipping of this partner base must overcome a free energy barrier, which constitutes one element contributing to changes in the thermodynamic properties induced by the DNA damage and sensed by the recognition protein. We explored this hypothesis by computing complete flipping free energy profiles for two lesions derived from the procarcinogenic polycyclic aromatic hydrocarbons (PAHs), dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P), R-trans-anti-DB[a,l]P-N6-dA (R-DB[a,l]P-dA) and R-trans-anti-B[a]P-N6-dA (R-B[a]P-dA), and the corresponding unmodified duplex. The DB[a,l]P and B[a]P adducts differ in number and organization of their aromatic rings. We integrate these results with prior profiles for the R-trans-anti-DB[a,l]P-dG adduct (Zheng, H. et al. (2010) Chem. Res. Toxicol.23, 1868-1870). All adopt conformational themes involving intercalation of the PAH aromatic ring system into the DNA duplex; however, R-DB[a,l]P-dA and R-B[a]P-dA intercalate from the major groove, while R-DB[a,l]P-dG intercalates from the minor groove. These structural differences produce different computed van der Waals stacking interaction energies between the flipping partner base with the lesion aromatic ring system and adjacent bases; we find that the better the stacking, the higher the relative flipping free energy barrier and hence lower flipping probability. The better relative NER susceptibilities correlate with greater ease of flipping in these three differently intercalated lesions. In addition to partner base flipping, the Rad4/Rad23 crystal structure shows that a protein-β-hairpin, BHD3, intrudes from the major groove side between the DNA strands at the lesion site. We present a molecular modeling study for the R-DB[a,l]P-dG lesion in Rad4/Rad23 showing BHD3 β-hairpin intrusion with lesion eviction, and we hypothesize that lesion steric effects play a role in the recognition of intercalated adducts.

UR - http://www.scopus.com/inward/record.url?scp=84880311470&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880311470&partnerID=8YFLogxK

U2 - 10.1021/tx400156a

DO - 10.1021/tx400156a

M3 - Article

VL - 26

SP - 1115

EP - 1125

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 7

ER -