Challenges and advances in the computational modeling of biological phosphate hydrolysis

We discuss the challenges and advances in modeling phosphate ester hydrolysis, and its implications for understanding biological phosphate transfer.

Catalytic Capacity of Diaza-Crown Ether Lanthanum Complexes with Varied Ligands for Phosphate Ester Hydrolysis in Different Media

Two diaza-crown ether compounds, 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane (L0) and its derivative with double acetamide side arms 2,2'-(1,4,10,13-teteaoxa-7,16-diazacyclooctadecane-7,16-diyl)diacetamide (L), and the corresponding two lanthanum complexes were synthesised and characterised. The catalytic capacity of the lanthanum complexes was investigated for the hydrolysis of bis(4-nitrophenyl) phosphate ester (BNPP) in aqueous solution and in CTAB micelles. Kinetic studies show that the catalytic efficiency of complex LaL is obviously higher than that of complex LaL0, and introducing acetamide into the ring of the diaza-crown ether can improve the catalytic ability of the complexes for BNPP hydrolysis. A rate enhancement of about two times was observed for the complex–micelle in contrast with the complex–water system for BNPP catalytic hydrolysis. The optimal pH for the catalytic reaction in the two kinds of media systems show an approximately 0.4 pH unit difference. The two complexes possess higher thermostability, and are more stable in the micelle than in aqueous solution. Based on the results and their analysis, a catalytic mechanism with cooperation of acetamide is proposed.

Exploiting parameter space in MOFs: a 20-fold enhancement of phosphate-ester hydrolysis with UiO-66-NH2

Using the enzymatic mechanism of phosphoesterase as a template, we were able to modify a metal–organic framework such that the hydrolysis rates were 50 times faster than previously demonstrated with UiO-66.

Why nature really chose phosphate

Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.