Conformational selection or induced fit: A flux description of reaction mechanism
Open accessAbstract
The mechanism of ligand binding coupled to conformational changes in macromolecules has recently attracted considerable interest. The 2 limiting cases are the “induced fit” mechanism (binding first) or “conformational selection” (conformational change first). Described here are the criteria by which the sequence of events can be determined quantitatively. The relative importance of the 2 pathways is determined not by comparing rate constants (a common misconception) but instead by comparing the flux through each pathway. The simple rules for calculating flux in multistep mechanisms are described and then applied to 2 examples from the literature, neither of which has previously been analyzed using the concept of flux. The first example is the mechanism of conformational change in the binding of NADPH to dihydrofolate reductase. The second example is the mechanism of flavodoxin folding coupled to binding of its cofactor, flavin mononucleotide. In both cases, the mechanism switches from being dominated by the conformational selection pathway at low ligand concentration to induced fit at high ligand concentration. Over a wide range of conditions, a significant fraction of the flux occurs through both pathways. Such a mixed mechanism likely will be discovered for many cases of coupled conformational change and ligand binding when kinetic data are analyzed by using a flux-based approach.
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For bacterial phosphotriesterase, maltose binding protein, choline oxidase, cytochrome bc1 complex, and many lid-gated enzymes, closed and open conformations are in equilibrium prior to ligand binding, permitting conformational selection at different catalytic steps.
“Conformational sampling for bacterial phosphotriesterase,443 maltose binding protein,444 and choline oxidase,445 cytochrome bc1 complex,446 and many other lid-gated enzymes indicated that the closed and open conformations are in equilibrium prior to ligand binding, permitting a conformational selection pathway at different catalytic steps.447”
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 [447]
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- Authors
- Hammes, G. G., Chang, Y.-C., & Oas, T. G.
- Affiliations
- Duke University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-08-18
- Volume
- 106
- Issue
- 33
- Pages
- 13737-13741
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2728963
- OpenAlex
- W2041000185
- Cited by
- 577
- References
- 50
- Citations by year
- 2026: 28 · 2025: 36 · 2024: 22 · 2023: 35 · 2022: 34 · 2021: 49 · 2020: 29 · 2019: 30 · 2018: 24 · 2017: 37 · 2016: 39 · 2015: 29 · 2014: 37 · 2013: 46 · 2012: 43
- FWCI
- 13.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM081666, R01GM061367)
- National Institute of Allergy and Infectious Diseases (P30AI064518)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- conformational selection, induced fit, ligand binding, conformational change, flux analysis, reaction mechanism, NADPH binding, dihydrofolate reductase, flavin mononucleotide
- MeSH terms
- Algorithms, Chemistry, Flavins, Kinetics, Ligands, Models, Chemical, Models, Theoretical, Molecular Conformation, NADP, Magnetic Resonance Spectroscopy, Protein Conformation, Tetrahydrofolate Dehydrogenase, Protein Folding, Desulfovibrio desulfuricans
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