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• Protein folding and unfolded states
• Recognition and repair of DNA damage
• Drug Discovery / Disease
• HIV/AIDS
• Tuberculosis
• Cancer
• Simulation methodologies
• Conformational sampling methods
• Force Field Development

Recognition and repair of DNA damage

(supported by a grant from the National Cancer Inst.)

  DNA is a major target of oxidative damage which, in turn, has been linked to human diseases associated with aging, including cancer. 8-oxoguanine (8OG) is one of the most common forms of oxidative DNA damage; failure to repair this lesion prior to DNA replication leads to G:C to A:T transversion mutations in bacterial and mammalian cells. Accurate repair of DNA damage is critical to the survival of all living organisms. In E. coli, Fpg (MutM), MutY and MutT work in concert to counter the potentially deleterious effects of 8OG. Fpg is an 8-oxoguanine-DNA glycosylase/AP lyase which excises 8OG from oxidatively damaged DNA. Selecting 8-oxoG as a model lesion, we are exploring the relationship between the structure of oxidatively damaged DNA and the mechanism of action of enzymes engaged in DNA replication and repair. We analyze the structural features of oxidatively-damaged DNA that confer recognition, the binding of 8-oxoguanine by repair enzymes and the translocation between DNA and enzyme and explore the functional groups and enzymatic mechanisms of the DNA glycosylases involved in these processes.

 In collaboration with the lab of Orlando Scharer at Stony Brook, we also study nitrogen mustards (HN2) and their analogs, which are a cytotoxic class of bifunctional alkylating agents that form various DNA crosslinks. Among the adducts that form from the reaction of these compounds with DNA, DNA interstrand crosslinks (ICLs) cause the greatest cytotoxicity to the cell.  ICLs form covalent bridges between two complementary strands of DNA thereby inhibiting essential processes such as DNA replication and transcription.  Various DNA repair pathways, including NER (nucleotide excision repair), homologous recombination and translesion synthesis work together to repair ICLs, but the details of how repair is achieved are not understood. In particular, the relationship between the structure of the ICL and its repair are not known. The ability to predict and characterize how ICLs influence DNA structure will provide opportunities to address this issue.  More extensive knowledge of the recognition events may lead to the development of more effective chemotherapeutic agents.  

Our recent publications on this topic:

Computational Analysis of the Mode of Binding of 8-Oxoguanine to Formamidopyrimidine-DNA Glycosylase
Kun Song, Viktor Hornak, Carlos de los Santos, Arthur P. Grollman, and Carlos Simmerling
Biochemistry; 2006; 45(36) pp 10886 - 10894
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/bi060380m

Molecular Mechanics Parameters for the FapydG DNA lesion
Kun Song, Viktor Hornak, Carlos de los Santos, Arthur P. Grollman, and Carlos Simmerling
Journal of Computational Chemistry; In press