The evolution of multiple active site configurations in a designed enzyme

Nan Sook Hong, Dušan Petrović, Richmond Lee, Ganna Gryn’ova, Miha Purg, Jake Saunders, Paul Bauer, Paul D. Carr, Ching Yeh Lin, Peter D. Mabbitt, William Zhang, Timothy Altamore, Chris Easton, Michelle L. Coote, Shina C.L. Kamerlin, Colin J. Jackson

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)
31 Downloads (Pure)


Developments in computational chemistry, bioinformatics, and laboratory evolution have facilitated the de novo design and catalytic optimization of enzymes. Besides creating useful catalysts, the generation and iterative improvement of designed enzymes can provide valuable insight into the interplay between the many phenomena that have been suggested to contribute to catalysis. 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.

Original languageEnglish
Article number3900
Number of pages10
JournalNature Communications
Issue number1
Publication statusPublished - 25 Sept 2018
Externally publishedYes


  • Computational models
  • Synthetic chemistry methodology
  • Molecular conformation


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