| Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions. | |
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MedLine Citation:
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PMID: 21831831 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Andrew J Adamczyk; Jie Cao; Shina C L Kamerlin; Arieh Warshel |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-08-10 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-08-29 Completed Date: 2011-10-27 Revised Date: 2012-02-23 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 14115-20 Citation Subset: IM |
Affiliation:
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Department of Chemistry (Seeley G. Mudd 418), University of Southern California, 3620 McClintock Avenue, Los Angeles, CA 90089, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Biocatalysis* Entropy Models, Molecular Pliability Protein Conformation Static Electricity* Tetrahydrofolate Dehydrogenase / chemistry*, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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GM024492/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 1.5.1.3/Tetrahydrofolate Dehydrogenase |
| Comments/Corrections | |
Comment In:
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Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15013-4
[PMID:
21885737
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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