Abstract
Dephosphorylation of phosphotyrosine by the low molecular weight protein tyrosine phosphatase proceeds via nucleophilic substitution at the phosphorous atom yielding a covalent enzyme-substrate intermediate that is subsequently hydrolyzed. The reactive nucleophile is the thiolate anion of Cys12. Here we calculate the free energy profiles of putative reaction mechanisms by molecular dynamics and free energy perturbation simulations, utilizing the empirical valence bond method to describe the reaction potential surface. Binding calculations addressing the protonation state of the enzyme-substrate complex are also performed. The calculations give a consistent picture of the catalytic mechanism that is compatible with experimental data.
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