C. Alhambra et al., WALDEN-INVERSION-ENFORCED TRANSITION-STATE STABILIZATION IN A PROTEIN-TYROSINE-PHOSPHATASE, Journal of the American Chemical Society, 120(16), 1998, pp. 3858-3866
The initial step of the dephosphorylation reaction of a tyrosine phosp
hate substrate catalyzed by the low molecular weight bovine protein ty
rosine phosphatase (BPTP) has been studied, making use of a combined q
uantum mechanical and molecular mechanical approach in molecular dynam
ics simulations. It was found that the enzyme favors a dianion substra
te in the dephosphorylation reaction, which is consistent with experim
ents but in contrast to a recent mechanistic proposal involving a mono
anion phosphate. The computed activation free energy is ca. 14 kcal/mo
l, in accord with the activation parameters determined in the present
study from stopped-flow kinetics experiments. Structural analyses supp
ort the finding that BPTP catalyzes dephosphorylation reactions by sta
bilizing the transition state through Walden-inversion-enforced hydrog
en-bonding interactions during the S(N)2 process.