University of Texas- Arlington
March 8th, 2019 – Spring Seminar
Time and Location: Noon in Meyerhoff Chemistry, Room 120
Host: Dr. Songon An
“Multiscale Simulation Studies of Catalytic and Regulatory Mechanisms of Protein Tyrosine Kinases”
Protein tyrosine kinases (PTKs) play central roles in broad range of signal transduction pathways that control cell homeostasis, and have been important targets for developing therapeutic approaches for human diseases, especially cancer. In the cell, various allosteric mechanisms regulate the catalytic activities of PTKs, but the molecular mechanisms by which their catalytic activities are controlled remain poorly understood. To advance our understanding of kinase catalysis and allostery, we have developed novel multiscale simulation approaches by combining quantum mechanics with statistical mechanics. The developed methods were applied to elucidate the catalytic mechanism of insulin receptor kinase (IRK) and the mechanism of how its phosphorylation of the activation loop influences the enzyme’s catalytic activity. The simulations revealed an important link between protein dynamics and the regulation of catalytic activity by kinase phosphorylation. To examine if similar roles of protein dynamics in kinase allostery present in other kinases, the simulation study was extended to insulin-like growth factor 1 kinase (IGF-1RK), an IRK homolog, and determined free energy landscapes encompassing the entire catalytic cycle of the enzyme, both in the presence and absence of activation loop phosphorylation. The simulations showed that the kinase phosphorylation affects each step in the IGF-1RK catalytic cycle, including conformational change, substrate binding/product release and catalytic phosphoryl transfer, which were mediated by changes in protein dynamics and side chain interactions. In the presentation, details of the simulation results are presented and discussed.