NMR dynamics experiments and molecular dynamics simulations with YopH and PTP1B have shown the acid loop samples both open and closed conformations throughout the catalytic cycle, although the equilibrium poise changes from favoring the loop-open form in the free enzymes, to the closed state when a ligand is bound. NMR data also reveal a correlation between the respective rates of WPD-loop closure and the cleavage rate (step 1 in Figure ) in YopH and PTP1B. The conserved Asp residue in the WPD loop serves critical roles in both chemical steps; as an acid in the first step, and a general base in the second. Why should an enzyme family evolve with a catalytic residue on a mobile loop? Evolutionarily, factors that affect loop motion could serve a regulatory purpose at the cost of maximally efficient catalysis. YopH, the fastest PTP yet characterized, exhibits the fastest WPD-loop dynamics measured to date. However, the "fastest" positioning of the Asp residue would be to place it on a non-mobile element, permanently in the optimal catalytic position. Such a stationary positioning is thought to be the case in many PTP family members on the basis of X-ray structures that show only a single conformation, although future work may reveal unsuspected mobility. Yet, those enzymes exhibit turnover numbers in the single digits, an order of magnitude slower than PTP1B, and two orders of magnitude slower than YopH. Variation in the rate of phosphoenzyme hydrolysis could reflect differences in optimal positioning of the Asp carboxylate, as well as the obvious role played by dynamics. Because only the WPD-loop closed conformation can perform catalysis, factors affecting the dynamic equilibria in Scheme 1, such as amino acid sequence within the WPD-loop, or interactions of the loop with surrounding regions of the protein, will affect both catalytic steps.