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.
authors.affiliation: Department of Biology, New York University, New York, New York 10003, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Zheng
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Cai
authors.forename: Shuang
authors.initials: S
authors.lastname: Ding
authors.forename: Yijin
authors.initials: Y
authors.lastname: Tang
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kropachev
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: Shenglong
authors.initials: S
authors.lastname: Wang
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Zhang
authors.forename: Suse
authors.initials: S
authors.lastname: Broyde
mesh_terms: D001580:Benzopyrenes / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: D001580:Benzopyrenes; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C513287:RAD23B protein, human; C086984:XPC protein, human; C021146:dibenzo(a,i)pyrene; D004247:DNA; D045643:DNA Repair Enzymes