(465c) Determining Stable Dimeric Configurations of Proteins Using Molecular Simulations

Protein dimerization is a mechanism through which proteins participate in numerous biological signal pathways. The objective of this work is to determine stable dimeric configurations of proteins via free energy analysis using advanced molecular simulation techniques. Specifically, our focus is the dimerization of interferon regulatory factor 3 (IRF3) protein, which is known to play an important role in the innate immune response. Innate immune system response is the first line of defense when a pathogen invades our body. Many times, viruses can inhibit IRF3 dimerization, or aberrant dimerization of IRF3 can lead to many diseases, including autoimmune disease, cancer, and diabetes. Therefore, identifying the stable dimeric configurations of IRF3 as a function of its phosphorylation state will allow for the development of therapeutics for the treatment of these diseases. Using metadynamics, we have studied the stable dimeric configurations for different phosphorylation states and have identified key interactions that stabilize these configurations.