Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions
Adamczyk, Andrew J ; Cao, Jie ; Kamerlin, Shina C L LU
and Warshel, Arieh
(2011)
In Proceedings of the National Academy of Sciences of the United States of America
108(34).
p.20-14115
- Abstract
The proposal that enzymatic catalysis is due to conformational fluctuations has been previously promoted by means of indirect considerations. However, recent works have focused on cases where the relevant motions have components toward distinct conformational regions, whose population could be manipulated by mutations. In particular, a recent work has claimed to provide direct experimental evidence for a dynamical contribution to catalysis in dihydrofolate reductase, where blocking a relevant conformational coordinate was related to the suppression of the motion toward the occluded conformation. The present work utilizes computer simulations to elucidate the true molecular basis for the experimentally observed effect. We start by... (More)
The proposal that enzymatic catalysis is due to conformational fluctuations has been previously promoted by means of indirect considerations. However, recent works have focused on cases where the relevant motions have components toward distinct conformational regions, whose population could be manipulated by mutations. In particular, a recent work has claimed to provide direct experimental evidence for a dynamical contribution to catalysis in dihydrofolate reductase, where blocking a relevant conformational coordinate was related to the suppression of the motion toward the occluded conformation. The present work utilizes computer simulations to elucidate the true molecular basis for the experimentally observed effect. We start by reproducing the trend in the measured change in catalysis upon mutations (which was assumed to arise as a result of a "dynamical knockout" caused by the mutations). This analysis is performed by calculating the change in the corresponding activation barriers without the need to invoke dynamical effects. We then generate the catalytic landscape of the enzyme and demonstrate that motions in the conformational space do not help drive catalysis. We also discuss the role of flexibility and conformational dynamics in catalysis, once again demonstrating that their role is negligible and that the largest contribution to catalysis arises from electrostatic preorganization. Finally, we point out that the changes in the reaction potential surface modify the reorganization free energy (which includes entropic effects), and such changes in the surface also alter the corresponding motion. However, this motion is never the reason for catalysis, but rather simply a reflection of the shape of the reaction potential surface.
(Less)
- author
- Adamczyk, Andrew J
; Cao, Jie
; Kamerlin, Shina C L
LU
and Warshel, Arieh
- publishing date
- 2011-08-23
- type
- Contribution to journal
- publication status
- published
- keywords
- Biocatalysis, Entropy, Models, Molecular, Pliability, Protein Conformation, Static Electricity, Tetrahydrofolate Dehydrogenase/chemistry
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 108
- issue
- 34
- pages
- 6 pages
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:21831831
- scopus:80052149070
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.1111252108
- language
- English
- LU publication?
- no
- id
- 372ab674-eb06-4df4-a22d-c7ab219e6846
- date added to LUP
- 2025-01-11 22:09:19
- date last changed
- 2025-07-14 08:07:21
@article{372ab674-eb06-4df4-a22d-c7ab219e6846,
abstract = {{<p>The proposal that enzymatic catalysis is due to conformational fluctuations has been previously promoted by means of indirect considerations. However, recent works have focused on cases where the relevant motions have components toward distinct conformational regions, whose population could be manipulated by mutations. In particular, a recent work has claimed to provide direct experimental evidence for a dynamical contribution to catalysis in dihydrofolate reductase, where blocking a relevant conformational coordinate was related to the suppression of the motion toward the occluded conformation. The present work utilizes computer simulations to elucidate the true molecular basis for the experimentally observed effect. We start by reproducing the trend in the measured change in catalysis upon mutations (which was assumed to arise as a result of a "dynamical knockout" caused by the mutations). This analysis is performed by calculating the change in the corresponding activation barriers without the need to invoke dynamical effects. We then generate the catalytic landscape of the enzyme and demonstrate that motions in the conformational space do not help drive catalysis. We also discuss the role of flexibility and conformational dynamics in catalysis, once again demonstrating that their role is negligible and that the largest contribution to catalysis arises from electrostatic preorganization. Finally, we point out that the changes in the reaction potential surface modify the reorganization free energy (which includes entropic effects), and such changes in the surface also alter the corresponding motion. However, this motion is never the reason for catalysis, but rather simply a reflection of the shape of the reaction potential surface.</p>}},
author = {{Adamczyk, Andrew J and Cao, Jie and Kamerlin, Shina C L and Warshel, Arieh}},
issn = {{1091-6490}},
keywords = {{Biocatalysis; Entropy; Models, Molecular; Pliability; Protein Conformation; Static Electricity; Tetrahydrofolate Dehydrogenase/chemistry}},
language = {{eng}},
month = {{08}},
number = {{34}},
pages = {{20--14115}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions}},
url = {{http://dx.doi.org/10.1073/pnas.1111252108}},
doi = {{10.1073/pnas.1111252108}},
volume = {{108}},
year = {{2011}},
}