Protein kinases (PKs) form a large family of enzymes that catalyze targeted phosphorylation on protein substrates. In addition, they play a central role in cell signaling and human disease. Typically, the 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 the catalytic activity of PK remains poorly characterized. To enable a systematic investigation of the mechanisms of kinase catalysis, ligand binding and conformational change, we have developed new, efficient multiscale QM/MM and free energy simulation methods. By applying these methods, we investigated 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 both in the presence and absence of A-loop phosphorylation. The determined free energy landscapes have identified an important principle for the allosteric regulation of kinase activity, affecting the entire IGF-1RK catalytic cycle, including conformational activation, ligand binding and catalytic phosphoryl transfer. At the meeting, the results of these studies will be presented, along with recent new findings on the connection between slow protein motions and kinase catalysis.

Connection between protein conformational dynamics and catalysis in protein kinases: Insights from multiscale simulations

2019 Fall National Meeting

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