Both protein dynamics and ligand concentration can shift the binding mechanism between conformational selection and induced fit
Open accessAbstract
This study aimed to shed light on the long debate over whether conformational selection (CS) or induced fit (IF) is the governing mechanism for protein-ligand binding. The main difference between the two scenarios is whether the conformational transition of the protein from the unbound form to the bound form occurs before or after encountering the ligand. Here we introduce the IF fraction (i.e., the fraction of binding events achieved via IF), to quantify the binding mechanism. Using simulations of a model protein-ligand system, we demonstrate that both the rate of the conformational transition and the concentration of ligand molecules can affect the IF fraction. CS dominates at slow conformational transition and low ligand concentration. An increase in either quantity results in a higher IF fraction. Despite the many-body nature of the system and the involvement of multiple, disparate types of dynamics (i.e., ligand diffusion, protein conformational transition, and binding reaction), the overall binding kinetics over wide ranges of parameters can be fit to a single exponential, with the apparent rate constant exhibiting a linear dependence on ligand concentration. The present study may guide future kinetics experiments and dynamics simulations in determining the IF fraction.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Evidence points to the conformational selection binding mechanism, which allows one to precompute the conformational ensemble of the interacting molecule(s) and dock the separate conformers with limited conformational search.
“In a long-standing debate between the proponents of the “induced-fit” and the “conformational selection” binding mechanisms [21–23], the evidence pointing to the latter allows one to precompute the conformational ensemble of the interacting molecule(s) and dock the separate conformers with limited conformational search [24,25].”
From Challenges in protein docking (2020) · cites this paper as [23]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.
Monod, J., Wyman, J., & Changeux, J. (1965) · Journal of Molecular Biology · doi:10.1016/s0022-2836(65)80285-6 · Cited by 7,681 · see citing works
Perutz, M. F. (1970) · Nature · doi:10.1038/228726a0 · Cited by 2,931 · see citing works
Brownian dynamics with hydrodynamic interactions
Ermak, D., & McCammon, J. (1978) · The Journal of Chemical Physics · doi:10.1063/1.436761 · Cited by 2,238 · see citing works
Application of a Theory of Enzyme Specificity to Protein Synthesis.
Koshland, D. (1958) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.44.2.98 · Cited by 2,140 · see citing works
The role of dynamic conformational ensembles in biomolecular recognition
Boehr, D. D., Nussinov, R., & Wright, P. E. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.232 · Cited by 2,008 · see citing works
Solution structure of a calmodulin-target peptide complex by multidimensional NMR
Ikura, M., Clore, G. M., Gronenborn, A. M., Zhu, G., Klee, C. B., & Bax, A. (1992) · Science · doi:10.1126/science.1585175 · Cited by 1,268 · see citing works
Csermely, P., Palotai, R., & Nussinov, R. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.04.009 · Cited by 821 · see citing works
Miller, M., Schneider, J., Sathyanarayana, B. K., et al. (1989) · Science · doi:10.1126/science.2686029 · Cited by 688 · see citing works
Conformational selection or induced fit: A flux description of reaction mechanism
Hammes, G. G., Chang, Y.-C., & Oas, T. G. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907195106 · Cited by 577 · see citing works
Müller, C. W., & Schulz, G. E. (1992) · Journal of Molecular Biology · doi:10.1016/0022-2836(92)90582-5 · Cited by 528 · see citing works
Spurlino, J. C., Lu, G.-Y., & Quiocho, F. A. (1990) · Worldwide Protein Data Bank · doi:10.2210/pdb1mbp/pdb · Cited by 461 · see citing works
Spurlino, J. C., Lu, G. Y., & Quiocho, F. A. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)67774-4 · Cited by 454 · see citing works
Open-to-closed transition in apo maltose-binding protein observed by paramagnetic NMR
Tang, C., Schwieters, C. D., & Clore, G. M. (2007) · Nature · doi:10.1038/nature06232 · Cited by 416 · see citing works
Conformational selection or induced fit? 50 years of debate resolved
Changeux, J., & Edelstein, S. J. (2011) · F1000 Biology Reports · doi:10.3410/b3-19 · Cited by 272 · see citing works
Arora, K., & Brooks, C. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706443104 · Cited by 269 · see citing works
A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein
Silva, D., Bowman, G. R., Sosa‐Peinado, A., & Huang, X. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002054 · Cited by 224 · see citing works
Conformational Motions Regulate Phosphoryl Transfer in Related Protein Tyrosine Phosphatases
Whittier, S. K., Hengge, A. C., & Loria, J. P. (2013) · Science · doi:10.1126/science.1241735 · Cited by 215 · see citing works
Stochastically gated diffusion-influenced reactions
Szabó, A., Shoup, D., Northrup, S. H., et al. (1982) · The Journal of Chemical Physics · doi:10.1063/1.444397 · Cited by 213 · see citing works
Binding of flexible ligands to macromolecules
Burgen, A. S. V., Roberts, G. C. K., & Feeney, J. (1975) · Nature · doi:10.1038/253753a0 · Cited by 199 · see citing works
Sullivan, S. M., & Holyoak, T. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805364105 · Cited by 167 · see citing works
Zhou, H. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2009.11.029 · Cited by 161 · see citing works
Self-citationManipulation of ligand binding affinity by exploitation of conformational coupling.
Marvin, J. S., & Hellinga, H. W. (2001) · Nature Structural Biology · doi:10.1038/nsb0901-795 · Cited by 153 · see citing works
Gated binding of ligands to proteins
McCammon, J. A., & Northrup, S. H. (1981) · Nature · doi:10.1038/293316a0 · Cited by 149 · see citing works
Dynamics and mechanisms of coupled protein folding and binding reactions
Kiefhaber, T., Bachmann, A., & Jensen, K. S. (2012) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.09.010 · Cited by 136 · see citing works
Conformational Selection Is a Dominant Mechanism of Ligand Binding
Vogt, A. D., & Di, E. (2013) · Biochemistry · doi:10.1021/bi400929b · Cited by 133 · see citing works
A single-molecule dissection of ligand binding to a protein with intrinsic dynamics
Kim, E., Lee, S.-H., Jeon, A., Choi, J. M., Lee, H., Hohng, S., & Kim, H. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1213 · Cited by 120 · see citing works
Millet, Ó., Hudson, R. D. A., & Kay, L. E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2134311100 · Cited by 112 · see citing works
Kinetics of hemoglobin and transition state theory.
Szabó, A. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.5.2108 · Cited by 106 · see citing works
Bucher, D., Grant, B. J., & McCammon, J. A. (2011) · Biochemistry · doi:10.1021/bi201481a · Cited by 100 · see citing works
Many Local Motions Cooperate to Produce the Adenylate Kinase Conformational Transition
Daily, M. D., Phillips, G. N., & Cui, Q. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.05.015 · Cited by 93 · see citing works
Conformational changes and drug action.
Burgen, A. S. (1981) · PubMed · Cited by 90 · see citing works
Theory and simulation of the time-dependent rate coefficients of diffusion-influenced reactions
Zhou, H., & Szabó, A. (1996) · Biophysical Journal · doi:10.1016/s0006-3495(96)79437-7 · Cited by 85 · see citing works
Self-citationZhou, H. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1101555108 · Cited by 84 · see citing works
Self-citationChen, J., Dima, R. I., & Thirumalai, D. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.08.047 · Cited by 74 · see citing works
Eaton, W. A., Henry, E. R., & Hofrichter, J. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.10.4472 · Cited by 72 · see citing works
Ligand Concentration Regulates the Pathways of Coupled Protein Folding and Binding
Daniels, K. G., Tonthat, N. K., McClure, D. R., Chang, Y., Liu, X., Schumacher, M. A., Fierke, C. A., Schmidler, S. C., & Oas, T. G. (2013) · Journal of the American Chemical Society · doi:10.1021/ja4086726 · Cited by 71 · see citing works
Kinetics of diffusion-influenced reactions studied by Brownian dynamics
Zhou, H. (1990) · The Journal of Physical Chemistry · doi:10.1021/j100388a010 · Cited by 70 · see citing works
Self-citationTheory and Simulation of Stochastically-Gated Diffusion-Influenced Reactions
Zhou, H., & Szabó, A. (1996) · The Journal of Physical Chemistry · doi:10.1021/jp952376i · Cited by 68 · see citing works
Self-citationProtein dynamics and conformational selection in bidirectional signal transduction
Nussinov, R., & Ma, B. (2012) · BMC Biology · doi:10.1186/1741-7007-10-2 · Cited by 65 · see citing works
Conformational Selection in G-Proteins: Lessons from Ras and Rho
Grant, B. J., McCammon, J. A., & Gorfe, A. A. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2010.10.020 · Cited by 54 · see citing works
Clore, G. M. (2013) · Biophysical Chemistry · doi:10.1016/j.bpc.2013.08.006 · Cited by 44 · see citing works
Theory and simulation on the kinetics of protein–ligand binding coupled to conformational change
Cai, L., & Zhou, H. (2011) · The Journal of Chemical Physics · doi:10.1063/1.3561694 · Cited by 39 · see citing works
Self-citationRivas‐Pardo, J. A., Herrera-Morandé, A., Castro‐Fernández, V., Fernández, F. J., Vega, M. C., & Guixé, V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066687 · Cited by 28 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Perutz MF (1970) Stereochemistry of cooperative effects in haemoglobin. Nature 228(5273):726-739.
Cited by
Sorted by citations
Protein Allostery and Conformational Dynamics
Guo, J., & Zhou, H.-X. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00590 · Cited by 484 · see citing works
Self-citationDi Cera, E. (2020) · Biophysics Reviews · doi:10.1063/5.0020997 · Cited by 73 · see citing works
Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs
Nussinov, R., Zhang, M., Maloney, R., Liu, Y., Tsai, C.-J., & Jang, H. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167569 · Cited by 66 · see citing works
Vakser, I. A. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.07.001 · Cited by 62 · see citing works
- Authors
- Greives, N., & Zhou, H.-X.
- Affiliations
- Florida State University (US)
- ORCID
- Zhou, Huan-Xiang
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-06-30
- Volume
- 111
- Issue
- 28
- Pages
- 10197-10202
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4104862
- OpenAlex
- W2040934203
- Cited by
- 82
- References
- 43
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 2 · 2020: 10 · 2019: 6 · 2018: 9 · 2017: 5 · 2016: 16 · 2015: 9 · 2014: 3
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM 58187, R01GM058187)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- protein-ligand binding, conformational selection, induced fit, binding mechanism, ligand concentration, binding kinetics, apparent rate constant, ligand diffusion, protein dynamics
- MeSH terms
- Kinetics, Ligands, Models, Chemical, Proteins, Molecular Dynamics Simulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
