Tuesday, March 7th, 2017
1:00 p.m. Room 202 MRB
Professor Christos Deligkaris
Assistant Professor of Physics, University of Southern Indiana, Evansville, Indiana
Predicting small molecule-binding to DNA with docking methods: validation, improvement and applications
DNA interacts with small molecules, from water to endogenous reactive oxygen and nitrogen species, environmental mutagens and carcinogens, and pharmaceutical anticancer molecules. Understanding and predicting the physico-chemical interactions of small molecules with DNA is key not only for the comprehension of molecular-level events that lead to carcinogenesis and other diseases, but also for the rational design of drugs that target DNA. We validated a popular docking method (AutoDock 4) that includes a physics-based free energy function and a Lamarckian Genetic Algorithm, for the prediction of small molecule geometries upon physical binding to DNA. We noticed that quite often the binding site closest to the experimental geometry was not the one with the lowest free energy but the one found with the highest frequency among all computational simulations. An empirical conformational entropy term based on the docking frequency was added to the free energy function in order to improve the binding site predictions. These results, as well as results from applying the docking methodology to the tobacco carcinogens BPDE and NNK, will be presented and discussed.