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Theoretical Study of Specific Hydrogen-Bonding Effects on the Bridging P−OR Bond Strength of Phosphate Monoester Dianions

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journal contribution
posted on 13.03.2008, 00:00 by Nathalie Iché-Tarrat, Jean-Claude Barthelat, Alain Vigroux
It has been proposed that the driving force for the initial phosphoryl transfer step of protein tyrosine phosphatases (PTPases) could be activation of the substrate ROPO32- by means of an enforced hydrogen-bonding interaction between an aspartic general acid and the bridging oxygen atom O (Zhang et al. Biochemistry 1995, 34, 16088−16096). The potential catalytic effect of this type of interaction, with regard to P−OR bond cleavage, was investigated computationally through simple model systems in which an efficient intramolecular hydrogen bond can take place between a H-bond donor group and the bridging oxygen atom of the dianionic phosphate. The dielectric effect of the environment (ε = 1, 4, and 78) was also explored. The results indicate that this interaction causes significant lengthenings of the scissile P−OR bond in all media but with more extreme effects observed in the low dielectric fields ε = 1 and ε = 4. It is interesting that, in all cases examined, this interaction actually contributes to stabilize the reactant state while causing its P−OR bond to lengthen. Overall, our results support the idea that this specific hydrogen-bonding situation might well be used by PTPases as an important driving force for promoting phosphoryl transfer reactions through highly dissociative transition states.

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