(294c) Sequence Specific Recognition of Cancer Drug-DNA Adducts by HMGB1a Repair Protein

Platinum-based anti-cancer drugs are designed to covalently bind to DNA to form adducts in order to inhibit continuous cell growth. Differential recognition of various drug-DNA adducts by repair proteins, like HMGB1a, has been linked to differential tumor resistance. We use molecular simulations to show the molecular reasons behind why HMGB1a differentially binds to adducts of cisplatin and oxaliplatin, two drugs widely used for treatment of cancer. We also explain why the binding affinity of HMGB1a for these two drug-DNA adducts is dependent on sequence context, i.e. the bases flanking the drug-DNA adduct. Our work has shown that the structure of drug-DNA bound to HMGB1a protein cannot explain differential recognition [1]. Instead the differences in conformational dynamics of the Cp-DNA and Ox-DNA in various sequence contexts before the protein binds and the free energy of deforming (e.g. bending and minor groove opening) the drug-DNA during protein binding explain the differential protein binding affinity for the two drugs in the various sequence contexts [1, 2].

[1] R. M. Elder and A. Jayaraman. "Role of structure and dynamics of DNA with cisplatin and oxaliplatin adducts in various sequence contexts on binding of HMGB1a." Mol. Sim. (in press), 2012.

[2] R. M. Elder and A. Jayaraman. "Sequence specific recognition of cancer drug-DNA adducts by HMGB1a repair protein." Biophys. J. (in press), 2012.