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

The use of quantum mechanics/molecular mechanics simulations to study the free energy landscape of the water activation at the catalytic site of mitochondria! 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 beta-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 beta-Glu 188 support this role.