<i>Ab</i> <i>Initio</i> Exploration of the Phosphoryl Transfer Reaction Provides Insights into Interpreting Models of S_N2 Mechanisms

Phosphoryl transfer from nucleoside triphosphates (NTPs), which drives many chemical processes in living organisms, is a putatively concerted (S_N2) process. However, some computational studies have found dissociative (S_N1) 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.