STUDYING THE INTERACTION OF CANCER AND THROMBOSIS THERAPEUTICS WITH PROTEIN AND DNA

Abstract

In my dissertation research I have used atomic force microscopy (AFM), simulations and molecular biology to investigate different classes of therapeutics. Many cancer drugs bind to DNA and inhibit replication. We have AFM and simulations, based on the worm-like chain model (WLC), to study DNA conformational changes due to its interaction with two cancer drugs, cisplatin and Pt-Acramtu. We found that cisplatin induces a 36º bend angle for a cisplatin-GG adduct and 0 - 19º for a cisplatin-AG adduct. Overall DNA flexibility did not change due to these interactions with a single cisplatin molecule, but DNA softens around the damage site. The intercalating drug Pt-Acramtu lengthens DNA by 0.45 - 0.6 nm/drug molecule, but does not change DNA flexibility, for 2-30 % drug to base pair ratio. The higher doses of Pt-Acramtu induced DNA loops and aggregation, and the highest doses caused DNA double-strand breaks.