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Biochemistry. 2013 Feb 5;52(5):959-66. doi: 10.1021/bi301109x. Epub 2013 Jan 25.

Simulation of catalytic water activation in mitochondrial F1-ATPase using a hybrid quantum mechanics/molecular mechanics approach: an alternative role for β-Glu 188.

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Molecular Modelling Group, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), C/Nicolás Cabrera 1, Cantoblanco, Madrid, Spain.


The use of quantum mechanics/molecular mechanics simulations to study the free energy landscape of the water activation at the catalytic site of mitochondrial F(1)-ATPase affords us insight into the generation of the nucleophile OH(-) prior to ATP hydrolysis. As a result, the ATP molecule was found to be the final proton acceptor. In the simulated pathway, the transfer of a proton to the nucleotide was not direct but occurred via a second water molecule in a manner similar to the Grotthuss mechanism proposed for proton diffusion. Residue β-Glu 188, previously described as the putative catalytic base, was found to be involved in the stabilization of a transient hydronium ion during water activation. Simulations in the absence of the carboxylate moiety of β-Glu 188 support this role.

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