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

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

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Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid), Madrid, Spain.

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  • Biophys J. 2012 Mar 7;102(5):1234.


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.

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