Base flipping free energy profiles for damaged and undamaged DNA

Han Zheng; Yuqin Cai; Shuang Ding; Yijin Tang; Konstantin Kropachev; Yanzi Zhou; Lihua Wang; Shenglong Wang; Nicholas E. Geacintov; Yingkai Zhang; Suse Broyde

doi:10.1021/tx1003613

Base flipping free energy profiles for damaged and undamaged DNA

Han Zheng, Yuqin Cai, Shuang Ding, Yijin Tang, Konstantin Kropachev, Yanzi Zhou, Lihua Wang, Shenglong Wang, Nicholas E. Geacintov, Yingkai Zhang, Suse Broyde

Research output: Contribution to journal › Article › peer-review

Abstract

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-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.

Original language	English (US)
Pages (from-to)	1868-1870
Number of pages	3
Journal	Chemical research in toxicology
Volume	23
Issue number	12
DOIs	https://doi.org/10.1021/tx1003613
State	Published - Dec 20 2010

ASJC Scopus subject areas

Toxicology

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10.1021/tx1003613

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Base flipping free energy profiles for damaged and undamaged DNA. / Zheng, Han; Cai, Yuqin; Ding, Shuang; Tang, Yijin; Kropachev, Konstantin; Zhou, Yanzi; Wang, Lihua; Wang, Shenglong; Geacintov, Nicholas E.; Zhang, Yingkai ; Broyde, Suse.

In: Chemical research in toxicology, Vol. 23, No. 12, 20.12.2010, p. 1868-1870.

Research output: Contribution to journal › Article › peer-review

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title = "Base flipping free energy profiles for damaged and undamaged DNA",

abstract = "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-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.",

author = "Han Zheng and Yuqin Cai and Shuang Ding and Yijin Tang and Konstantin Kropachev and Yanzi Zhou and Lihua Wang and Shenglong Wang and Geacintov, {Nicholas E.} and Yingkai Zhang and Suse Broyde",

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doi = "10.1021/tx1003613",

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AU - Zheng, Han

AU - Cai, Yuqin

AU - Ding, Shuang

AU - Tang, Yijin

AU - Kropachev, Konstantin

AU - Zhou, Yanzi

AU - Wang, Lihua

AU - Wang, Shenglong

AU - Geacintov, Nicholas E.

AU - Zhang, Yingkai

AU - Broyde, Suse

PY - 2010/12/20

Y1 - 2010/12/20

N2 - 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-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.

AB - 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-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.

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