Transition-state Ensemble in Enzyme Catalysis: Possibility, Reality, or Necessity?
Abstract
Proteins are not rigid structures; they are dynamic entities, with numerous conformational isomers (substates). The dynamic nature of protein structures amplifies the structural variation of the transition state for chemical reactions performed by proteins. This suggests that utilizing a transition state ensemble to describe chemical reactions involving proteins may be a useful representation. Here we re-examine the nature of the transition state of protein chemical reactions (enzyme catalysis), considering both recent developments in chemical reaction theory (Marcus theory for SN2 reactions), and protein dynamics effects. The classical theory of chemical reactions relies on the assumption that a reaction must pass through an obligatory transition-state structure. The widely accepted view of enzymatic catalysis holds that there is tight binding of the substrate to the transition-state structure, lowering the activation energy. This picture, may, however, be oversimplified. The real meaning of a transition state is a surface, not a single saddle point on the potential energy surface. In a reaction with a "loose" transition-state structure, the entire transition-state region, rather than a single saddle point, contributes to reaction kinetics. Consequently, here we explore the validity of such a model, namely, the enzymatic modulation of the transition-state surface. We examine its utility in explaining enzyme catalysis. We analyse the possibility that instead of optimizing binding to a well-defined transition-state structure, enzymes are optimized by evolution to bind efficiently with a transition-state ensemble, with a broad range of activated conformations. For enzyme catalysis, the key issue is still transition state (ensemble) stabilization. The source of the catalytic power is the modulation of the transition state. However, our definition of the transition state is the entire transition-state surface rather just than a single well-defined structure. This view of the transition-state ensemble is consistent with the nature of the protein molecule, as embodied and depicted in the protein energy landscape of folding, and binding, funnels.
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Enzymes are optimized by evolution to exploit conformational ensembles to recognize substrates and stabilize transition states.
“Enzymes are optimized by evolution to exploit conformational ensembles to recognize their substrates and stabilize the transition states,70,209 and both experimental and theoretical evidence indicates that enzyme conformational transitions are highly organized which increases enzyme specificity and efficiency.133,399,433–435”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [70]
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- Authors
- MA, B., KUMAR, S., TSAI, C.-J., HU, Z., & NUSSINOV, R.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Tel Aviv University (IL)
- Venue
- Journal of Theoretical Biology
- Publisher
- Elsevier BV
- Published
- 2000-04
- Volume
- 203
- Issue
- 4
- Pages
- 383-397
- ISSN
- 0022-5193 (ISSN-L)
- OpenAlex
- W2095148095
- Cited by
- 86
- References
- 63
- Citations by year
- 2025: 6 · 2024: 5 · 2023: 8 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 2
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Theoretical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01co056000-057)
- National Cancer Institute (N01 CO 56000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Keywords
- enzyme catalysis, transition state ensemble, protein dynamics, conformational isomers, Marcus theory, SN2 reaction, activation energy, transition state stabilization, protein energy landscape, binding free energy, reaction kinetics
- MeSH terms
- Animals, Catalysis, Enzymes, Humans, Models, Chemical, Protein Conformation, Proteins
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