University of Texas at Arlington
Department of Chemistry and Biochemistry
October 18, 2019 – FALL SEMINAR
Time and Location: 12 Noon in Meyerhoff Chemistry Building, Room 120
Host: Dr. Songon An
“Multiscale Simulations of Kinase Conformational Dynamics, Catalysis and Regulation”
Protein kinases (PKs) form a large family of enzymes that catalyze targeted phosphorylation on protein substrates. In the cell, they play a central role in cell signaling and human diseases, especially cancers. Typically, conformational activation of PK is achieved by phosphorylation within the enzyme, such as the activation loop (A-loop), while the resting state kinase adopts the inactive conformation. Despite the well-established conformational activation mechanism, the molecular mechanism that relates large-scale conformational dynamics to PK’s catalytic activity remains poorly characterized. To enable a systematic investigation of the mechanisms of kinase catalysis, allostery and conformational dynamics, we have developed novel multiscale simulation approaches combining quantum mechanics with statistical mechanics. The developed methods were applied to elucidate the catalytic mechanism of insulin receptor kinase (IRK) and the influence of A-loop phosphorylation on its catalytic activity. This study revealed the important role of fast, equilibrium protein dynamics in the regulation of the catalytic activity of IRK. In parallel, the free energy landscapes encompassing the entire functional cycle of insulin-like growth factor 1 kinase (IGF-1RK), a homolog of IRK, were determined. The determined free energy landscapes have identified an important principle for the allosteric regulation of kinase activity, which affects each step in the IGF-1RK catalytic cycle, including conformational activation, ligand binding and catalytic phosphoryl transfer. In this seminar, the results of these studies will be presented, along with recent new findings on the connection between slow protein motions and kinase catalysis.