Finally, PTP1B (Figure ) is a protein tyrosine phosphatase (PTP) that plays an important role in the regulation of signal transduction , and is a major drug target for treating type 2 diabetes and obesity , and a major cancer therapeutic target . This enzyme catalyzes a two-step cleavage/hydrolysis mechanism, in which an active site cysteine first acts as a nucleophile attacking the phosphate group of the substrate, followed by rate-limiting hydrolysis of the resulting phospho-cysteine intermediate, with involvement of an aspartic acid located on a mobile loop, the WPD-loop, in acid-base catalysis . As with TPI, the WPD-loop undergoes a substantial conformational change from a catalytically active loop-open to a catalytically-active loop-closed conformation to position the aspartic acid side chain in an optimal position for catalysis . The dynamical behavior of this loop has been suggested by both experimental and computational work to be important for determining the activity of PTPs more broadly . Taken together, the three systems studied here cover a span of chemical reactions, isomerization, ring-opening, and phosphoryl transfer, against which to test the performance of Q-RepEx.