Protein Flexibility and Preorganization in the Design of Enzymes. The Kemp Elimination Catalyzed by HG3.17

© 2015 American Chemical Society. A recently designed enzyme, HG3.17, obtained by directed evolution, has shown a catalytic activity close to natural enzymes. Hybrid QM/MM molecular dynamics simulations for the Kemp elimination in this new enzyme have provided a deep insight into the origin of its catalytic efficiency. In this case, we have first demonstrated the presence of different conformations with significantly different reactivity. The larger reactivity is related with a better electrostatic preorganization of the environment that creates a more favorable electrostatic potential for the reaction to proceed. In HG3.17, efforts to improve the catalytic properties must be focused in possible mutations increasing the preorganization and decreasing the reorganization around the oxyanion hole. Mutations should be considered not only in the first shell of residues but in further shells since protein electrostatics is a long-range property. The present work stresses the fact that not all features of catalysis can be revealed of a single structure derived from X-ray diffraction. (Figure Presented).