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Abstract
Phosphate and sulfate esters have important roles in regulating cellular processes. However, while there has been substantial experimental and computational investigation of the mechanisms and the transition states involved in phosphate ester hydrolysis, there is far less work on sulfate ester hydrolysis. Here, we report a detailed computational study of the alkaline hydrolysis of diaryl sulfate diesters, using different DFT functionals as well as mixed implicit/explicit solvation with varying numbers of explicit water molecules. We consider the impact of the computational model on computed linear free-energy relationships (LFER) and the nature of the transition states (TS) involved. We obtain good qualitative agreement with experimental LFER data when using a pure implicit solvent model and excellent agreement with experimental kinetic isotope effects for all models used. Our calculations suggest that sulfate diester hydrolysis proceeds through loose transition states, with minimal bond formation to the nucleophile and bond cleavage to the leaving group already initiated. Comparison to prior work indicates that these TS are similar in nature to those for the alkaline hydrolysis of neutral arylsulfonate monoesters or charged phosphate diesters and fluorophosphates. Obtaining more detailed insights into the transition states involved assists in understanding the selectivity of enzymes that hydrolyze these reactions.
Highlights
We show that the slope of the calculated linear free-energy relationships (LFER) is highly dependent both on the functional used and on the number of explicit water molecules introduced into the system but that in all cases, we are able to obtain good agreement with experimental kinetic isotope effects (KIE) irrespective of the functional used or the number of water molecules
In prior work on the hydrolysis of phosphate monoester dianions and sulfate monoester monoanions, we demonstrated that the inclusion of explicit water molecules into the system can have a substantial impact on the energies and geometries of the resulting optimized structures and the ability to reproduce all the experimental data, including isotope effects.[25]
Our prior work has focused on using mixed explicit/implicit solvation to study the attack of a neutral nucleophile (H2O) on charged electrophiles,[25,34,38] whereas the current study focuses on the attack of a charged nucleophile (OH−) on neutral sulfate diesters
Summary
The hydrolysis of both phosphate and sulfate esters is ubiquitous in biology and plays important roles in numerous cellular processes, including in particular the regulation of cellular signaling processes.[1,2] unsurprisingly, the enzymes that catalyze these reactions are involved in a range of human diseases, making them important drug targets.[3−5] In addition, many phosphatases possess promiscuous sulfatase activity,[6] and such promiscuity is likely to be of evolutionary significance for these enzymes.[7−11] While there has been substantial research focus on understanding enzymatic phosphate and sulfate hydrolysis (for reviews, see, e.g., refs 2, 6, 12, and the references cited therein), understanding the corresponding non-enzymatic hydrolysis of these compounds is important in order to provide insights into the fundamental chemistry and the nature of the transition states involved. There has been far less research effort invested into studying non-enzymatic sulfate hydrolysis, and, in particular, while there have been a number of elegant experimental studies of sulfate ester hydrolysis, corresponding computational studies have been very limited Both experimental[11,13−22] and computational[23−25] studies of sulfate monoester hydrolysis suggest that the transition states for these reactions are mechanistically similar to those of their corresponding phosphate monoesters, proceeding through concerted pathways with loose (concerted but dissociative in character) transition states, with little bond formation to the nucleophile and advanced bond cleavage to the leaving group, resulting in a SO3-like sulfuryl group. Studies of the pH dependence of these reactions show a broad pHindependent region between pH 4 and 1213,14,19,26 (where hydrolysis likely proceeds by S−O rather than C−O bond cleavage) and a hydrolysis rate that is accelerated under strongly acidic or basic conditions.[14,27] Computational comparison of the hydrolysis of p-nitrophenyl phosphate and sulfate monoesters provides a similar mechanistic picture for these reactions,[25] the transition state for the Received: February 19, 2020 Published: April 20, 2020
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