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Base flipping free energy profiles for damaged and undamaged DNA.

ABSTRACT: Lesion-induced thermodynamic destabilization is believed to facilitate ?-hairpin intrusion by the human XPC/hHR23B nucleotide excision repair (NER) recognition factor, accompanied by partner-base flipping, as suggested by the crystal structure of the yeast orthologue (Min, J. H., and Pavletich, N. P. (2007) Nature 449, 570-575). To investigate this proposed mechanism, we employed the umbrella sampling method to compute partner base flipping free energies for the repair susceptible 14R (+)-trans-anti-DB[a,l]P-N(2)-dG modified duplex 11-mer, derived from the fjord region polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene, and for the undamaged duplex. Our flipping free energy profiles show that the adduct has a lower flipping barrier by ?7.7 kcal/mol, consistent with its thermally destabilizing impact on the damaged DNA duplex and its susceptibility to NER.

SUBMITTER: Zheng H

PROVIDER: S-EPMC3071897 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Base flipping free energy profiles for damaged and undamaged DNA.

Zheng Han H Cai Yuqin Y Ding Shuang S Tang Yijin Y Kropachev Konstantin K Zhou Yanzi Y Wang Lihua L Wang Shenglong S Geacintov Nicholas E NE Zhang Yingkai Y Broyde Suse S

Chemical research in toxicology 20101201 12

Lesion-induced thermodynamic destabilization is believed to facilitate β-hairpin intrusion by the human XPC/hHR23B nucleotide excision repair (NER) recognition factor, accompanied by partner-base flipping, as suggested by the crystal structure of the yeast orthologue (Min, J. H., and Pavletich, N. P. (2007) Nature 449, 570-575). To investigate this proposed mechanism, we employed the umbrella sampling method to compute partner base flipping free energies for the repair susceptible 14R (+)-trans- ...[more]

PMID: 21090780

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Project description: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 ) Nature 449 , 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-N(6)-dA (R-DB[a,l]P-dA) and R-trans-anti-B[a]P-N(6)-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.

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Base flipping free energy profiles for damaged and undamaged DNA.

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Base flipping free energy profiles for damaged and undamaged DNA.

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