Date of Award
12-1-2024
Degree Name
Master of Science
Department
Physics
First Advisor
Poopalasingam, Sivakumar
Abstract
The interaction between the tumor suppression protein p53 and ubiquitin ligase MDM2 that negatively regulates p53, plays a crucial role in controlling cell growth in cancerous tissues. MDM2 binds p53 through the N-terminal transactivation domain of p53, inhibiting its transcription activity and promoting its degradation. This negative feedback loop maintains low p53 levels in normal cells. Disrupting the p53-MDM2 interaction in cancer cells is a promising approach for therapy. To explore the probable binding/unbinding pathway of p53 during the formation/dissociation of the p53-MDM2 complex, we performed a Molecular Dynamics (MD) investigation of the p53-MDM2 complex (PDB ID :1YCR). We investigated the potential of mean force (PMF) to understand the free energy landscape of the dissociation process. Additionally, we examined p53's stability and structural dynamics as its distance from MDM2 is varied. Furthermore, we mutated the protein p53 and obtained p53 based peptides that mimic p53. We also identified 10 inhibitors computationally and they were docked with MDM2. By using computational analysis, we studied structural stability of these p53 mimics and other inhibitors and carried out MD simulations combined with Umbrella Sampling simulations to study the dissociation energy of the complexes.
Access
This thesis is only available for download to the SIUC community. Current SIUC affiliates may also access this paper off campus by searching Dissertations & Theses @ Southern Illinois University Carbondale from ProQuest. Others should contact the interlibrary loan department of your local library or contact ProQuest's Dissertation Express service.