The Role of Gln61 in HRas GTP hydrolysis: a quantum mechanics/molecular mechanics study.
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.
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid), Madrid, Spain.
Fernando
F
Martín-García
Jesús Ignacio
JI
Mendieta-Moreno
Eduardo
E
López-Viñas
Paulino
P
Gómez-Puertas
Jesús
J
Mendieta
D001665:Binding Sites; D003198:Computer Simulation; D005998:Glycine / Q000737:chemistry*; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006868:Hydrolysis; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry*; D011789:Quantum Theory
D006160:Guanosine Triphosphate; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D005998:Glycine