期刊
BIOPHYSICAL JOURNAL
卷 102, 期 1, 页码 152-157出版社
CELL PRESS
DOI: 10.1016/j.bpj.2011.11.4005
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资金
- Spanish Ministerio de Ciencia e Innovacion [SAF2007-61926]
- Madrid Regional Authority [S-B1O-0260/2006-COMBACT]
- European Commission [FP7 HEALTH-F3-2009-223431]
- European Social Fund
- Fundacion Ramon Areces
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 H3O+ 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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