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

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of 'Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes: Energetic and structural relationships to nucleotide excision repair susceptibility'. Together they form a unique fingerprint.

  • Cite this