Investigation of interaction energies of topoisomerase I inhibitor: topotecan

Abstract

Topoisomerases (Top1) cut one or both strands of DNA and therefore bring changes in the topology of DNA. They are ubiquitous enzymes which are essential for the cellular regulation of DNA supercoiling caused by processes such as replication, transcription, and recombination. These enzymes also adjust the steady state level of DNA supercoiling in order to facilitate protein-DNA interactions. Because of their crucial roles in DNA replication, topoisomerases are the focus of many cancer research, as they are the sole target for several families of anti-cancer drugs that are typically medium size organic molecules. The drug chosen for this project is Topotecan (TPT) which belongs to Camptothecin (CPT) family of anticancer drugs. The main purpose of this research is the application of three major physical theories on mechanics, namely quantum, classical, and statistical, in a harmonious blend to focus on different aspects of the dynamic mechanism of the DNA-Topoisomerase and DNA-Topoisomerase-TPT molecular systems. The large scale atomistic studies have been conducted by Levent Sarı from Fatih University, they have been coupled with the electronic level calculations in this study. Quantum chemical methods used in this study are DFT and semi-empirical theory. Overall, in this project, we aimed to combine both electronic level static calculations (quantum chemical data based on the time-independent Schrödinger equation) and time dependent data obtained at the atomic level (molecular dynamical calculations), and have used them together to gain deeper understanding on Top1-TPT-DNA interactions.