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The evolution of multiple active site configurations in a designed enzyme

Hong, Nan-Sook ; Petrović, Dušan ; Lee, Richmond ; Gryn'ova, Ganna ; Purg, Miha ; Saunders, Jake ; Bauer, Paul ; Carr, Paul D ; Lin, Ching-Yeh and Mabbitt, Peter D , et al. (2018) In Nature Communications 9(1).
Abstract

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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
Catalytic Domain, Computer-Aided Design, Crystallography, X-Ray, Directed Molecular Evolution, Enzyme Stability, Enzymes/chemistry, Isoxazoles/chemistry, Models, Chemical, Molecular Dynamics Simulation, Molecular Structure, Static Electricity, Thermodynamics
in
Nature Communications
volume
9
issue
1
article number
3900
publisher
Nature Publishing Group
external identifiers
  • scopus:85053869480
  • pmid:30254369
ISSN
2041-1723
DOI
10.1038/s41467-018-06305-y
language
English
LU publication?
no
id
31eb3193-3c0d-49de-8cd2-6e02f182cb30
date added to LUP
2025-01-11 21:02:24
date last changed
2025-06-30 05:37:21
@article{31eb3193-3c0d-49de-8cd2-6e02f182cb30,
  abstract     = {{<p>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.</p>}},
  author       = {{Hong, Nan-Sook and Petrović, Dušan and Lee, Richmond and Gryn'ova, Ganna and Purg, Miha and Saunders, Jake and Bauer, Paul and Carr, Paul D and Lin, Ching-Yeh and Mabbitt, Peter D and Zhang, William and Altamore, Timothy and Easton, Chris and Coote, Michelle L and Kamerlin, Shina C L and Jackson, Colin J}},
  issn         = {{2041-1723}},
  keywords     = {{Catalytic Domain; Computer-Aided Design; Crystallography, X-Ray; Directed Molecular Evolution; Enzyme Stability; Enzymes/chemistry; Isoxazoles/chemistry; Models, Chemical; Molecular Dynamics Simulation; Molecular Structure; Static Electricity; Thermodynamics}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The evolution of multiple active site configurations in a designed enzyme}},
  url          = {{http://dx.doi.org/10.1038/s41467-018-06305-y}},
  doi          = {{10.1038/s41467-018-06305-y}},
  volume       = {{9}},
  year         = {{2018}},
}