The Role of Gln61 in HRas GTP Hydrolysis: A Quantum Mechanics/Molecular Mechanics Study

descriptionPublicationkeyboard_double_arrow_right Article , Other literature type 01 Jan 2012 English Publisher:Elsevier BVJournal:Biophysical Journal, volume 102, pages 152-157 (issn: 0006-3495,

Copyright policy )Funded by:EC | DIVINOCELL

Authors: Martín-García, Fernando; Mendieta-Moreno, Jesús Ignacio; López-Viñas, Eduardo; Gómez-Puertas, Paulino; Mendieta, Jesús;

doi: 10.1016/j.bpj.2011.11.4005

pmid: 22225809

pmc: PMC3250681

handle: 10261/115020

The Role of Gln61 in HRas GTP Hydrolysis: A Quantum Mechanics/Molecular Mechanics Study

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Abstract

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.

Related Organizations

Biomol Informatics (Spain)
Spain
Centro de Biología Molecular Severo Ochoa
Spain
Spanish National Research Council
Spain
Autonomous University of Madrid
Spain
BIOMOL-INFORMATICS SL
Spain

Keywords

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

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