Mechanism of triphosphate hydrolysis in aqueous solution: QM/MM simulations in water clusters

The Journal of Physical Chemistry. B
Bella L GrigorenkoAlexander V Nemukhin

Abstract

The mechanism of the hydrolysis reaction of the unprotonated methyl triphosphate (MTP) ester in water clusters has been modeled. The effective fragment potential based quantum mechanical-molecular mechanical (QM/MM) approach has been applied in the simulations. It is shown that the minimum energy reaction path is consistent with an assumption of a two-step dissociative-type process similar to the case of the guanosine triphosphate (GTP) hydrolysis in the Ras-GAP protein complex (Grigorenko, B. L.; Nemukhin, A. V.; Topol, I. A.; Cachau, R. E.; Burt, S. K. Proteins: Struct., Funct., Bioinf. 2005, 60, 495). At the first stage, a unified action of environmental molecular groups and the catalytic water molecule leads to a substantial spatial separation of the gamma-phosphate group from the rest of the molecule. At the second stage, inorganic phosphate H2PO4- is formed from water and the metaphosphate anion PO3- through the chain of proton transfers along hydrogen bonds. The estimated activation barriers for MTP in aqueous solution at both stages (20 and 14 kcal/mol) are substantially higher than the corresponding barriers for the GTP hydrolysis in the protein.

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Citations

May 9, 2008·European Biophysics Journal : EBJ·Alexander A Tulub, V E Stefanov
Jan 16, 2013·Quarterly Reviews of Biophysics·Shina C L KamerlinArieh Warshel
Jan 11, 2007·Journal of the American Chemical Society·Marco De VivoMichael L Klein
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Oct 21, 2009·Chemical Communications : Chem Comm·Satyan Sharma, André H Juffer
Apr 18, 2007·Proceedings of the National Academy of Sciences of the United States of America·Bella L GrigorenkoAlexander V Nemukhin
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