The Role of Gln61 in HRas GTP hydrolysis: a quantum mechanics/molecular mechanics study

Biophys J. 2012 Jan 4;102(1):152-7. doi: 10.1016/j.bpj.2011.11.4005. Epub 2012 Jan 3.


Activation of the water molecule involved in GTP hydrolysis within the HRas·RasGAP system is analyzed using a tailored approach based on hybrid quantum mechanics/molecular mechanics (QM/MM) simulation. A new path emerges: transfer of a proton from the attacking water molecule to a second water molecule, then a different proton is transferred from this second water molecule to the GTP. Gln(61) will stabilize the transient OH(-) and H(3)O(+) molecules thus generated. This newly proposed mechanism was generated by using, for the first time to our knowledge, the entire HRas-RasGAP protein complex in a QM/MM simulation context. It also offers a rational explanation for previous experimental results regarding the decrease of GTPase rate found in the HRas Q61A mutant and the increase exhibited by the HRas Q61E mutant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Glycine / chemistry*
  • Guanosine Triphosphate / chemistry*
  • Hydrolysis
  • Models, Chemical*
  • Models, Molecular*
  • Protein Binding
  • Proto-Oncogene Proteins p21(ras) / chemistry*
  • Quantum Theory


  • Guanosine Triphosphate
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Glycine