The evolution of multiple active site configurations in a designed enzyme – New Nature Communications Paper!



Congratulations to Nansook and everyone involved in this project! This has been a great collaboration with Lynn Kamerlin (Uppsala University), Chris Easton (ANU) and Michelle Coote’s (ANU) groups.

In this work, we follow changes in conformational sampling, electrostatic preorganization, and quantum tunneling along the evolutionary trajectory of a designed Kemp eliminase. We observe that in the Kemp Eliminase KE07, instability of the designed active site leads to the emergence of two additional active site configurations. Evolutionary conformational selection then gradually stabilizes the most efficient configuration, leading to an improved enzyme. This work exemplifies the link between conformational plasticity and evolvability and demonstrates that residues remote from the active sites of enzymes play crucial roles in controlling and shaping the active site for efficient catalysis.

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