Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid), Madrid, Spain.
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.
使用基于混合量子力学/分子力学（QM/MM）模拟的定制方法分析了 HRas·RasGAP 系统中参与 GTP 水解的水分子的激活。出现了一条新的路径：质子从攻击水分子转移到第二个水分子，然后从第二个水分子转移到 GTP。Gln（61）将稳定由此产生的瞬态 OH（-）和 H（3）O（+）分子。据我们所知，这是首次在 QM/MM 模拟环境中使用整个 HRas-RasGAP 蛋白复合物生成这种新提出的机制。它还为以前关于 HRas Q61A 突变体中 GTPase 速率降低和 HRas Q61E 突变体中增加的实验结果提供了合理的解释。
