The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70
Abstract
Side chain entropy and mutual entropy information between residue pairs have been calculated for two de novo designed Kemp eliminase enzymes, KE07 and KE70, and for their most improved versions at the end of laboratory directed evolution (LDE). Here, we find that entropy, not just enthalpy, helped to destabilize the preference for the reactant state complex of the designed enzyme as well as favoring stabilization of the transition state complex for the best LDE enzymes. Furthermore, residues with the highest side chain couplings as measured by mutual information, when experimentally mutated, were found to diminish or annihilate catalytic activity, some of which were far from the active site. In summary, our findings demonstrate how side chain fluctuations and their coupling can be an important design feature for de novo enzymes, and furthermore could be utilized in the computational steps in lieu of or in addition to the LDE steps in future enzyme design projects.
- Authors:
-
- Univ. of California, Berkeley, CA (United States). Dept. Chemical and Biomolecular Engineering
- Univ. of California, Berkeley, CA (United States). Dept. of Chemistry
- Univ. of California, Berkeley, CA (United States). Dept. of Bioengineering
- Univ. of California, Berkeley, CA (United States). Dept. Chemical and Biomolecular Engineering; Univ. of California, Berkeley, CA (United States). Dept. of Chemistry; Univ. of California, Berkeley, CA (United States). Dept. of Bioengineering; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Chemical Sciences Division
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1532176
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Physical Chemistry Chemical Physics. PCCP
- Additional Journal Information:
- Journal Volume: 18; Journal Issue: 28; Journal ID: ISSN 1463-9076
- Publisher:
- Royal Society of Chemistry
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Citation Formats
Bhowmick, Asmit, Sharma, Sudhir C., Honma, Hallie, and Head-Gordon, Teresa. The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70. United States: N. p., 2016.
Web. doi:10.1039/c6cp03622h.
Bhowmick, Asmit, Sharma, Sudhir C., Honma, Hallie, & Head-Gordon, Teresa. The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70. United States. https://doi.org/10.1039/c6cp03622h
Bhowmick, Asmit, Sharma, Sudhir C., Honma, Hallie, and Head-Gordon, Teresa. Fri .
"The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70". United States. https://doi.org/10.1039/c6cp03622h. https://www.osti.gov/servlets/purl/1532176.
@article{osti_1532176,
title = {The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70},
author = {Bhowmick, Asmit and Sharma, Sudhir C. and Honma, Hallie and Head-Gordon, Teresa},
abstractNote = {Side chain entropy and mutual entropy information between residue pairs have been calculated for two de novo designed Kemp eliminase enzymes, KE07 and KE70, and for their most improved versions at the end of laboratory directed evolution (LDE). Here, we find that entropy, not just enthalpy, helped to destabilize the preference for the reactant state complex of the designed enzyme as well as favoring stabilization of the transition state complex for the best LDE enzymes. Furthermore, residues with the highest side chain couplings as measured by mutual information, when experimentally mutated, were found to diminish or annihilate catalytic activity, some of which were far from the active site. In summary, our findings demonstrate how side chain fluctuations and their coupling can be an important design feature for de novo enzymes, and furthermore could be utilized in the computational steps in lieu of or in addition to the LDE steps in future enzyme design projects.},
doi = {10.1039/c6cp03622h},
journal = {Physical Chemistry Chemical Physics. PCCP},
number = 28,
volume = 18,
place = {United States},
year = {Fri Jun 24 00:00:00 EDT 2016},
month = {Fri Jun 24 00:00:00 EDT 2016}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 21 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Hidden alternative structures of proline isomerase essential for catalysis
journal, December 2009
- Fraser, James S.; Clarkson, Michael W.; Degnan, Sheena C.
- Nature, Vol. 462, Issue 7273
Dynamics and dissipation in enzyme catalysis
journal, September 2011
- Boekelheide, N.; Salomon-Ferrer, R.; Miller, T. F.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 39
A Monte Carlo Method for Generating Side Chain Structural Ensembles
journal, January 2015
- Bhowmick, Asmit; Head-Gordon, Teresa
- Structure, Vol. 23, Issue 1
Kemp elimination catalysts by computational enzyme design
journal, March 2008
- Röthlisberger, Daniela; Khersonsky, Olga; Wollacott, Andrew M.
- Nature, Vol. 453, Issue 7192, p. 190-195
Exploring challenges in rational enzyme design by simulating the catalysis in artificial kemp eliminase
journal, September 2010
- Frushicheva, M. P.; Cao, J.; Chu, Z. T.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 39
A Smoothed Backbone-Dependent Rotamer Library for Proteins Derived from Adaptive Kernel Density Estimates and Regressions
journal, June 2011
- Shapovalov, Maxim V.; Dunbrack, Roland L.
- Structure, Vol. 19, Issue 6
Optimization of reorganization energy drives evolution of the designed Kemp eliminase KE07
journal, May 2013
- Labas, A.; Szabo, E.; Mones, L.
- Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1834, Issue 5
Evaluation and ranking of enzyme designs: Evaluation and Ranking of Enzyme Designs
journal, July 2010
- Kiss, Gert; Röthlisberger, Daniela; Baker, David
- Protein Science, Vol. 19, Issue 9
Hydrophobic Potential of Mean Force as a Solvation Function for Protein Structure Prediction
journal, June 2007
- Lin, Matthew S.; Fawzi, Nicolas Lux; Head-Gordon, Teresa
- Structure, Vol. 15, Issue 6
Directed evolution of a fungal peroxidase
journal, April 1999
- Cherry, Joel R.; Lamsa, Michael H.; Schneider, Palle
- Nature Biotechnology, Vol. 17, Issue 4
The role of dynamic conformational ensembles in biomolecular recognition
journal, October 2009
- Boehr, David D.; Nussinov, Ruth; Wright, Peter E.
- Nature Chemical Biology, Vol. 5, Issue 11
Dynamic personalities of proteins
journal, December 2007
- Henzler-Wildman, Katherine; Kern, Dorothee
- Nature, Vol. 450, Issue 7172
Long-Range Intra-Protein Communication Can Be Transmitted by Correlated Side-Chain Fluctuations Alone
journal, September 2011
- DuBay, Kateri H.; Bothma, Jacques P.; Geissler, Phillip L.
- PLoS Computational Biology, Vol. 7, Issue 9
A hierarchy of timescales in protein dynamics is linked to enzyme catalysis
journal, November 2007
- Henzler-Wildman, Katherine A.; Lei, Ming; Thai, Vu
- Nature, Vol. 450, Issue 7171
Protein Design by Directed Evolution
journal, June 2008
- Jäckel, Christian; Kast, Peter; Hilvert, Donald
- Annual Review of Biophysics, Vol. 37, Issue 1
Conformational entropy in molecular recognition by proteins
journal, July 2007
- Frederick, Kendra King; Marlow, Michael S.; Valentine, Kathleen G.
- Nature, Vol. 448, Issue 7151
Is allostery an intrinsic property of all dynamic proteins?
journal, July 2004
- Gunasekaran, K.; Ma, Buyong; Nussinov, Ruth
- Proteins: Structure, Function, and Bioinformatics, Vol. 57, Issue 3
Comparison of multiple Amber force fields and development of improved protein backbone parameters
journal, November 2006
- Hornak, Viktor; Abel, Robert; Okur, Asim
- Proteins: Structure, Function, and Bioinformatics, Vol. 65, Issue 3
Induced allostery in the directed evolution of an enantioselective Baeyer-Villiger monooxygenase
journal, January 2010
- Wu, S.; Acevedo, J. P.; Reetz, M. T.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 7
Evaluation of Structural and Evolutionary Contributions to Deleterious Mutation Prediction
journal, September 2002
- Saunders, Christopher T.; Baker, David
- Journal of Molecular Biology, Vol. 322, Issue 4
How important are entropic contributions to enzyme catalysis?
journal, October 2000
- Villa, J.; Strajbl, M.; Glennon, T. M.
- Proceedings of the National Academy of Sciences, Vol. 97, Issue 22
Investigating and Engineering Enzymes by Genetic Selection
journal, September 2001
- Taylor, Sean V.; Kast, Peter; Hilvert, Donald
- Angewandte Chemie International Edition, Vol. 40, Issue 18
A Dynamic Knockout Reveals That Conformational Fluctuations Influence the Chemical Step of Enzyme Catalysis
journal, April 2011
- Bhabha, G.; Lee, J.; Ekiert, D. C.
- Science, Vol. 332, Issue 6026
Exploring protein fitness landscapes by directed evolution
journal, December 2009
- Romero, Philip A.; Arnold, Frances H.
- Nature Reviews Molecular Cell Biology, Vol. 10, Issue 12
Zur Chemie des Benz-α,β-isoxazols
journal, January 1926
- Lindemann, Hans; Thiele, Hans
- Justus Liebig's Annalen der Chemie, Vol. 449, Issue 1
Challenges and Advances in Validating Enzyme Design Proposals: The Case of Kemp Eliminase Catalysis
journal, May 2011
- Frushicheva, Maria P.; Cao, Jie; Warshel, Arieh
- Biochemistry, Vol. 50, Issue 18
Catalytic Mechanism and Performance of Computationally Designed Enzymes for Kemp Elimination
journal, November 2008
- Alexandrova, Anastassia N.; Röthlisberger, Daniela; Baker, David
- Journal of the American Chemical Society, Vol. 130, Issue 47
De novo design of biocatalysts
journal, April 2002
- Bolon, Daniel N.; Voigt, Christopher A.; Mayo, Stephen L.
- Current Opinion in Chemical Biology, Vol. 6, Issue 2
Restricted sidechain plasticity in the structures of native proteins and complexes: Restricted Sidechain Plasticity
journal, March 2011
- Fleishman, Sarel J.; Khare, Sagar D.; Koga, Nobuyasu
- Protein Science, Vol. 20, Issue 4
Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles
journal, August 2009
- McClendon, Christopher L.; Friedland, Gregory; Mobley, David L.
- Journal of Chemical Theory and Computation, Vol. 5, Issue 9
Analysis of Catalytic Residues in Enzyme Active Sites
journal, November 2002
- Bartlett, Gail J.; Porter, Craig T.; Borkakoti, Neera
- Journal of Molecular Biology, Vol. 324, Issue 1
Computational method to reduce the search space for directed protein evolution
journal, March 2001
- Voigt, C. A.; Mayo, S. L.; Arnold, F. H.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 7
Characterization of Proton-Transfer Catalysis by Serum Albumins
journal, February 2000
- Hollfelder, Florian; Kirby, Anthony J.; Tawfik, Dan S.
- Journal of the American Chemical Society, Vol. 122, Issue 6
Impact of distal mutations on the network of coupled motions correlated to hydride transfer in dihydrofolate reductase
journal, April 2005
- Wong, K. F.; Selzer, T.; Benkovic, S. J.
- Proceedings of the National Academy of Sciences, Vol. 102, Issue 19
Enzyme-like proteins by computational design
journal, November 2001
- Bolon, D. N.; Mayo, S. L.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 25
Evolutionary Optimization of Computationally Designed Enzymes: Kemp Eliminases of the KE07 Series
journal, March 2010
- Khersonsky, Olga; Röthlisberger, Daniela; Dym, Orly
- Journal of Molecular Biology, Vol. 396, Issue 4
NMR Relaxation Studies of the Role of Conformational Entropy in Protein Stability and Ligand Binding
journal, May 2001
- Stone, Martin J.
- Accounts of Chemical Research, Vol. 34, Issue 5
Improving catalytic function by ProSAR-driven enzyme evolution
journal, February 2007
- Fox, Richard J.; Davis, S. Christopher; Mundorff, Emily C.
- Nature Biotechnology, Vol. 25, Issue 3
Structural Reorganization and Preorganization in Enzyme Active Sites: Comparisons of Experimental and Theoretically Ideal Active Site Geometries in the Multistep Serine Esterase Reaction Cycle
journal, November 2008
- Smith, Adam J. T.; Müller, Roger; Toscano, Miguel D.
- Journal of the American Chemical Society, Vol. 130, Issue 46
De Novo Computational Design of Retro-Aldol Enzymes
journal, March 2008
- Jiang, L.; Althoff, E. A.; Clemente, F. R.
- Science, Vol. 319, Issue 5868
Side-Chain Conformational Heterogeneity of Intermediates in the Escherichia coli Dihydrofolate Reductase Catalytic Cycle
journal, May 2013
- Tuttle, Lisa M.; Dyson, H. Jane; Wright, Peter E.
- Biochemistry, Vol. 52, Issue 20
Precision is essential for efficient catalysis in an evolved Kemp eliminase
journal, October 2013
- Blomberg, Rebecca; Kries, Hajo; Pinkas, Daniel M.
- Nature, Vol. 503, Issue 7476
On the nature of allosteric transitions: A plausible model
journal, May 1965
- Monod, Jacque; Wyman, Jeffries; Changeux, Jean-Pierre
- Journal of Molecular Biology, Vol. 12, Issue 1
Reliable protein structure refinement using a physical energy function
journal, October 2010
- Lin, Matthew S.; Head-Gordon, Teresa
- Journal of Computational Chemistry, Vol. 32, Issue 4
Extraction of configurational entropy from molecular simulations via an expansion approximation
journal, July 2007
- Killian, Benjamin J.; Yundenfreund Kravitz, Joslyn; Gilson, Michael K.
- The Journal of Chemical Physics, Vol. 127, Issue 2
Optimization of the In-Silico-Designed Kemp Eliminase KE70 by Computational Design and Directed Evolution
journal, April 2011
- Khersonsky, Olga; Röthlisberger, Daniela; Wollacott, Andrew M.
- Journal of Molecular Biology, Vol. 407, Issue 3
Dynamic activation of protein function: A view emerging from NMR spectroscopy
journal, November 2001
- Wand, A. Joshua
- Nature Structural Biology, Vol. 8, Issue 11, p. 926-931
Accessing protein conformational ensembles using room-temperature X-ray crystallography
journal, September 2011
- Fraser, J. S.; van den Bedem, H.; Samelson, A. J.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 39
Design by Directed Evolution
journal, March 1998
- Arnold, Frances H.
- Accounts of Chemical Research, Vol. 31, Issue 3
Works referencing / citing this record:
The evolution of multiple active site configurations in a designed enzyme
journal, September 2018
- Hong, Nan-Sook; Petrović, Dušan; Lee, Richmond
- Nature Communications, Vol. 9, Issue 1
Computational optimization of electric fields for better catalysis design
journal, September 2018
- Welborn, Valerie Vaissier; Ruiz Pestana, Luis; Head-Gordon, Teresa
- Nature Catalysis, Vol. 1, Issue 9
Understanding the entropic effect in chorismate mutase reaction catalyzed by isochorismate-pyruvate lyase from Pseudomonas aeruginosa (PchB)
journal, January 2019
- Xie, Liangxu; Yang, Mingjun; Chen, Zhe-Ning
- Catalysis Science & Technology, Vol. 9, Issue 4