Cytomorphic Electrical Circuit Modeling of Tumor Suppressor p53 Protein Pathway

The tumor suppressor protein, p53, efficiently performs its role as ‘guardian of genome’ by repairing the damaged DNA and killing those, which are beyond repair. The p53 protein initiates two separate pathways depending on whether the DNA is damaged or not. Under damaged DNA condition, the p53 with the help of other proteins, ATM, Mdm2 and Wip1 participates in two negative feedback loops to control cell repair and apoptosis (cell death). In case of undamaged DNA environment, its primary negative regulator, Mdm2, degrades it to a harmless level. In this paper, the mechanisms of participation of individual proteins in p53-led pathways under normal and damaged DNA conditions are studied and their mathematical models are derived based on Michealis-Menten Kinetics and Law of Mass Action as Ordinary Differential Equations (ODE). Subsequently, the whole pathway is converted into a system model to study the variation of protein responses with time. Each block of the system model is equivalently converted into electrical circuit model. It is designed and simulated using Cadence 90 nm gpdk tool. The ODEs and System model are simulated using Matlab R2014a environment. The simulation result of system model is tantamount to original results from ODE and are verified with previous biological experiments and observations. The outputs of system model and circuit model resembles each other. The simulated results of all three methods show dynamic behavior of the proteins in the pathway which favorably matches their biological characteristics. For ease of computation of the ODEs, some assumptions are considered like initial concentrations of proteins and time delay. Here, we design the cytomorphic electrical circuit inspired by the functions and interaction of proteins in the biological p53 pathway. So, the dynamics of the pathway, can be easily studied in a cost-effective manner in dry lab without use of real p53 cell. This study helps in cancer treatment since p53 is an attractive therapeutic target for cancer therapy. The simulation results of the circuit can also be beneficial to the pharmaceutical industry to control drug dose for treatment of cancer disease.