Protein tyrosine kinases (PTKs) play essential roles in broad range of single transduction pathways regulating cell proliferation and metabolism.  Although every PTK carries out the same catalytic function, i.e., the transfer of a single phosphate group from ATP to target tyrosine residues in protein substrates, they function only at specific time and location.  This is achieved by controlling the access of the catalytically competent active conformation.  In insulin receptor kinase (IRK), one member of the PTK family, the activation of the catalytic activity of the enzyme is achieved by autophosphorylating its own activation loop upon receiving activation signal or constitutively by mutations.  Interestingly, kinetic measurements have shown that the reaction rate of the enzyme, in particular, the chemical step, increases with the increase of the activation loop phosphorylations.  However, the cause of this activation of catalytic activity is not known.  In our lab, we investigate the effects of the activation loop phosphorylations on the catalytic rates and reaction mechanism by a series of QM/MM simulation.  For the study, we first developed efficient multi-scale QM/MM methods for accurate description of the reacting system in the active site of the enzyme.  The developed methods are first tested to model reactions to show stability and accuracy of the developed methods and then applied to the reaction catalyzed by IRK.  To complement the QM/MM results, we also carried out multiple long MD simulations in the active conformation of IRK to elucidate the effects of activation loop phosphorylations on protein dynamics.  In this meeting, the results are presented and discussed.

Development of multi-scale QM/MM methods for studying the reaction catalyzed by protein tyrosine kinase

248th National Meeting (2014)

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