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Molecular Energetics of Clustered Damage Sites

Michel Dupuis, Principal Investigator

Funding Agency: U.S. Department of Energy, Low Dose Radiation Research Program

The goal of the Molecular Energetics of Clustered Damage Sites project at Pacific Northwest National Laboratory (PNNL) is to characterize the qualitative and quantitative similarities and differences in DNA repair characteristics of clustered damage sites caused by ionizing radiation and singly damaged sites produced by endogenous oxidative stress. Base-pairing rules and DNA structural and dynamic properties are qualitatively and quantitatively different for singly and multiply damaged DNA sites. Differences in the mutagenic properties of singly and multiply damaged DNA sites can be traced to local (less than about 10 base pairs) alterations in the energetics and structural properties of DNA. State-of-the-art computational chemistry (atomistic quantum molecular) models are being used to characterize the structure, energetics, and spectroscopy of singly and multiply damaged (clustered) DNA sites. As part of this project, researchers are:

  • constructing computational models of DNA lesions representative of those formed by endogenous processes and by low- and high-linear energy transfer (LET) radiation
  • calculating the (free) energy of models of damaged and undamaged nucleotides using quantum chemical and molecular dynamics simulations
  • extracting from the above computations sequence- and damage-specific (Boltzmann-based) probability distributions associated with key steps in the recognition and repair of singly and multiply damaged DNA sites as a link to higher-level Monte Carlo base and nucleotide excision repair models.

By contrasting molecular-level properties of multiply damaged sites with those of isolated damage sites, we will gain qualitative and quantitative insights into the way biological responses to ionizing radiation differ from responses to endogenous damage.

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