Mechanism of phosphoryl transfer in kinases investigated by semiempirical calculations

Authors

  • Michael C. Hutter,

    1. Max-Planck-Institute of Biophysics, Theoretical Biophysics, Kennedyallee 70, D-60596 Frankfurt, Germany
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  • Volkhard Helms

    Corresponding author
    1. Max-Planck-Institute of Biophysics, Theoretical Biophysics, Kennedyallee 70, D-60596 Frankfurt, Germany
    Current affiliation:
    1. Center of Bioinformatics, Saarland University, Gebäude 17.1, Postfach 15 11 50, D-66041 Saarbrücken, Germany
    • Max-Planck-Institute of Biophysics, Theoretical Biophysics, Kennedyallee 70, D-60596 Frankfurt, Germany
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Abstract

The reaction mechanism of the enzymatic phosphoryl transfer in active site model systems of three kinases has been studied previously by AM1 semiempirical molecular orbital calculations. The computed mechanism shows the synchronous shift of a proton to the transferred PO3 group in all our kinase model systems despite the chemical variety of the phosphoryl acceptors and the distinct differences of the associated energy profiles. Here, computed geometries are compared with X-ray crystallographic data and results of density functional calculations. Further, the presence of the transition-state analog aluminum fluoride was found to alter the protonation state of the phosphoryl acceptors. In combination with recent experimental studies we suggest that the concerted mechanism of phosphoryl transfer is common to all kinases. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003

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