# Ab Initio Exploration of the Phosphoryl Transfer Reaction Provides Insights into Interpreting Models of SN2 Mechanisms

## TL;DR

This paper explores how phosphoryl transfer reactions occur, finding that they are concerted processes influenced by environmental factors like solvent and electrostatic interactions.

## Contribution

The study provides new insights into the mechanism of phosphoryl transfer by combining computational modeling with analysis of bond orders and fractional progress.

## Key findings

- Phosphoryl transfer reactions are consistently concerted across various solvent conditions.
- Bond orders in the transition state decrease with increasing electrostatic and steric repulsion.
- Enzymatic phosphoryl transfer may benefit from favorable steric interactions and lower dielectric environments.

## Abstract

Phosphoryl transfer
from nucleoside triphosphates (NTPs), which
drives many chemical processes in living organisms, is a putatively
concerted (SN2) process. However, some computational studies
have found dissociative (SN1) character. In this work,
we model the hydrolysis of the terminal phosphoryl group of a magnesium-bound
methyl triphosphate using the ωB97X-D4//6-311++G­(d,p) level
of theory. We recapitulate experimental activation barriers for aqueous
hydrolysis. We also vary solvent conditions from an explicit water
shell in implicit water to implicit acetone and to implicit water
with lowered dielectric equal to that of acetone. In all environmental
conditions, we observed a concerted chemical mechanism, yet with decreased
bond orders in the transition state. Furthermore, these bond orders
decrease with increasing electrostatic repulsion and possibly steric
repulsion, suggesting that diffuse interactions dominate the transition
state and lead to underestimated bond orders. To quantitate the concerted
aspect, we combine fractional progress in bond length and bond order
for the transformation from the reactants to the products at the transition
state. We find that both the attacking nucleophile and leaving group
have similar sums of fractional progress. Additionally, enzymatic
phosphoryl transfer likely benefits from favorable steric interactions
and the lower dielectric expected in protein pockets compared to water