The creation of loop-grafted chimeras is a proven tool to study key mobile portions of proteins, providing valuable insight into protein function and evolvability. In addition, it is an increasingly popular tool to generate new enzymes with novel reactivities and specificities. For example, the grafting of multiple loops has been used to design and evolve β-lactamase activity in glyoxalase II and the role of protein motions in β-lactamase activity has been studied using chimeras of two class-A β-lactamases, TEM-1 and PSE-4. A chimera of ribonuclease A and a homologue was used to identify the role of protein flexibility in the rate-determining step and to identify conserved dynamical traits in the RNAse superfamily. The exchange of surface loops was shown to convert trypsin to a chymotrypsin-like protease. Chimeras of the Pseudomonas and Burkholderia homologs of the Rh1A enzyme have been a key tool in protein engineering and directed evolution studies. Related to this, modifications to a key active site loop in the (βα)8barrel isomerase of histidine biosynthesis HisA during a real time evolution experiment allow this enzyme to diverge into HisA specialists, bifunctional HisA/TrpF specialists (the latter being an important step of tryptophan biosynthesis), and TrpF specialists. Finally, there is growing interest in the role of loop dynamics in protein evolvability and loop engineering and grafting as a tool for protein design. Most of the work in the field of loop dynamics has centered on surface and lid loops that cover the active site and their functional role in substrate and cofactor binding, protein-protein interaction, and stability. Crystal structures with bound analogs of peptide substrates show the WPD-loop does not act as a lid covering the PTP active site, and loop closure does not prohibit diffusion of the substrate and product (or water molecules) in and out of the enzyme. Rather, the primary purpose of WPD-loop motion is positioning of the key catalytic Asp residue into the active site from the side, allowing substrate binding or leaving group departure after the first step to occur from either loop position. But, as highlighted in the kinetic scheme (Scheme 1), only the loopclosed states perform catalysis.