DNA damages: modeling & rationalize structure & reactivity
Elucidating the structure of damaged oligonucleotides as well as the mechanisms leading to lesions or conversely promoting repair is a fundamental challenge in chemical biology. With this workshop we plan to bring together leading experimentalists and theoreticians to give a most comprehensive picture of these processes, at a molecular and electronic level. We will also evidence how the structural modification of DNA, induced by damaged nucleobases or by sensitization, govern both the energy- and electron-transfer phenomena and the repair rate. This scientific challenge needs to combine efforts from cutting-edge spectroscopies and molecular modeling. In particular multiscale modeling going from explicit quantum description of ground and the excited states, to mesoscale coarse grain simulations passing through an atomistic classical description is fundamental to get a clear comprehension of all these fundamental mechanisms.
In particular we plan to tackle the following problems:
- Identify at an electronic level the non-covalent interactions governing DNA structure and dynamics and the role of the environment in its fine tuning. In that context the use of long-time scale dynamics (hundreds of ns) has to be tackled as well as the development of adequate force field also by a fruitful interplay with quantum chemistry.
- Monitoring DNA helical distortion and obtain accurate free energies of destabilization.
- Compare structural parameters obtained by spectroscopic techniques (Circular Dichroism, FRET, Luminescence, RMN) with molecular modeling.
- Modeling of non standard DNA structures such as G-quadruplexes, single strands, hairpins and elucidate the factors governing their stability.
- Study the interaction between DNA and histones and in general proteins.
- Unravel the structure and dynamics of DNA/sensitizers complexes, their dynamic evolution and the different interaction modes. Identifying possible selective non covalent modes and interpret their stability.
- Elucidate the chemical mechanism leading to radical DNA oxidation. Identification of products and key intermediates and of their main structural aspects
- Modeling the chemical reaction pathways taking into account environment and dynamic effects. Selectivity and sequence effects are particularly emphasized. One important case could be the elucidation of hydrogen abstraction mechanism that should require the use of high correlated methods.
- Discuss the validity of the different model systems in correctly reproducing the peculiar DNA reactivity. In particular the modeling of isolated damaged nucleobases to delineate the emergence of some trends should be considered.
- Modeling the excited states of the complexes DNA/sensitizers and compare them to the experimental evidences. Modeling the excited state potential energy landscape, both in the singlet and triplet manifolds and the effects of the environment in modulate their profile.
- Modeling the time evolution of the ground and the excited states leading to possible (photo-)chemical adducts.
- Produce a fine modeling and interpretation of sequence effects, also by comparison with the important amount of data.
- Modeling and interpret the interaction of DNA with repair enzymes. In particular elucidating the reasons, both structural and electronic, of the lack of repair of some lesions.
- Provide ideas for the rational design of novel anticancer drugs.