Protein Conformational Populations and Functionally Relevant Substates
Open accessAbstract
Functioning proteins do not remain fixed in a unique structure, but instead they sample a range of conformations facilitated by motions within the protein. Even in the native state, a protein exists as a collection of interconverting conformations driven by thermodynamic fluctuations. Motions on the fast time scale allow a protein to sample conformations in the nearby area of its conformational landscape, while motions on slower time scales give it access to conformations in distal areas of the landscape. Emerging evidence indicates that protein landscapes contain conformational substates with dynamic and structural features that support the designated function of the protein. Nuclear magnetic resonance (NMR) experiments provide information about conformational ensembles of proteins. X-ray crystallography allows researchers to identify the most populated states along the landscape, and computational simulations give atom-level information about the conformational substates of different proteins. This ability to characterize and obtain quantitative information about the conformational substates and the populations of proteins within them is allowing researchers to better understand the relationship between protein structure and dynamics and the mechanisms of protein function. In this Account, we discuss recent developments and challenges in the characterization of functionally relevant conformational populations and substates of proteins. In some enzymes, the sampling of functionally relevant conformational substates is connected to promoting the overall mechanism of catalysis. For example, the conformational landscape of the enzyme dihydrofolate reductase has multiple substates, which facilitate the binding and the release of the cofactor and substrate and catalyze the hydride transfer. For the enzyme cyclophilin A, computational simulations reveal that the long time scale conformational fluctuations enable the enzyme to access conformational substates that allow it to attain the transition state, therefore promoting the reaction mechanism. In the long term, this emerging view of proteins with conformational substates has broad implications for improving our understanding of enzymes, enzyme engineering, and better drug design. Researchers have already used photoactivation to modulate protein conformations as a strategy to develop a hypercatalytic enzyme. In addition, the alteration of the conformational substates through binding of ligands at locations other than the active site provides the basis for the design of new medicines through allosteric modulation.
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A protein can exist in one conformation in its inactive state and another in its active state.
“However, a protein can exist in one conformation in its “inactive” state and another in its “active” state.53–56”
From AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function (2021) · cites this paper as [53]
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Cites
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
Einfluss der Configuration auf die Wirkung der Enzyme
Fischer, E. (1894) · Berichte der deutschen chemischen Gesellschaft · doi:10.1002/cber.18940270364 · Cited by 1,841 · see citing works
Biomolecular simulation: a computational microscope for molecular biology.
Dror, R., Dirks, R. M., Grossman, J. P., Xu, H., & Shaw, D. (2012) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-042910-155245 · Cited by 1,176 · see citing works
ModBase, a database of annotated comparative protein structure models, and associated resources
Pieper, U., Webb, B., Barkan, D. T., Schneidman‐Duhovny, D., Schlessinger, A., Braberg, H., Yang, Z., Meng, E., Pettersen, E. F., Huang, C. C., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq1091 · Cited by 1,069 · see citing works
A hierarchy of timescales in protein dynamics is linked to enzyme catalysis
Henzler‐Wildman, K. A., Lei, M., Thai, V., Kerns, S. J., Karplus, M., & Kern, D. (2007) · Nature · doi:10.1038/nature06407 · Cited by 1,067 · see citing works
Intrinsic dynamics of an enzyme underlies catalysis
Eisenmesser, E., Millet, Ó., Labeikovsky, W., Korzhnev, D., Wolf-Watz, M., Bosco, D. A., Skalicky, J., Kay, L., & Kern, D. (2005) · Nature · doi:10.1038/nature04105 · Cited by 1,057 · see citing works
Recognition Dynamics Up to Microseconds Revealed from an RDC-Derived Ubiquitin Ensemble in Solution
Lange, O. F., Lakomek, N., Farès, C., Schroeder, G. F., Walter, K. F. A., Becker, S., Meiler, J., Grubmüller, H., Griesinger, C., & de Groot, B. L. (2008) · Science · doi:10.1126/science.1157092 · Cited by 1,044 · see citing works
The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis
Boehr, D. D., McElheny, D., Dyson, H. J., & Wright, P. E. (2006) · Science · doi:10.1126/science.1130258 · Cited by 958 · see citing works
Hidden alternative structures of proline isomerase essential for catalysis
Fraser, J. S., Clarkson, M. W., Degnan, S. C., Erion, R., Kern, D., & Alber, T. (2009) · Nature · doi:10.1038/nature08615 · Cited by 509 · see citing works
Kiss, G., Çelebi‐Ölçüm, N., Moretti, R., Baker, D. A., & Houk, K. N. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201204077 · Cited by 493 · see citing works
Bhabha, G., Lee, J., Ekiert, D. C., Gam, J., Wilson, I. A., Dyson, H. J., Benkovic, S. J., & Wright, P. E. (2011) · Science · doi:10.1126/science.1198542 · Cited by 462 · see citing works
An NMR Perspective on Enzyme Dynamics
Boehr, D. D., Dyson, H. J., & Wright, P. E. (2006) · Chemical Reviews · doi:10.1021/cr050312q · Cited by 460 · see citing works
Tethering: Fragment-Based Drug Discovery
Erlanson, D. A., Wells, J. A., & Braisted, A. C. (2004) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.33.110502.140409 · Cited by 385 · see citing works
Flexibility, Diversity, and Cooperativity: Pillars of Enzyme Catalysis
Hammes, G. G., Benkovic, S. J., & Hammes‐Schiffer, S. (2011) · Biochemistry · doi:10.1021/bi201486f · Cited by 275 · see citing works
Theozymes and compuzymes: theoretical models for biological catalysis
Tantillo, D. J., Chen, J., & Houk, K. N. (1998) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(98)80112-9 · Cited by 264 · see citing works
Protein elastic network models and the ranges of cooperativity
Yang, L., Song, G., & Jernigan, R. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902159106 · Cited by 260 · see citing works
Discovery of an allosteric site in the caspases
Hardy, J. A., Lam, J. W., Nguyen, J. T., O'Brien, T., & Wells, J. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404781101 · Cited by 236 · see citing works
Protein folded states are kinetic hubs
Bowman, G., & Pande, V. (2010) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1003962107 · Cited by 216 · see citing works
Enzymes: An integrated view of structure, dynamics and function
Agarwal, P. K. (2006) · Microbial Cell Factories · doi:10.1186/1475-2859-5-2 · Cited by 204 · see citing works
Self-citationMultidomain assembled states of Hck tyrosine kinase in solution
Yang, S., Blachowicz, L., Makowski, L., & Roux, B. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004569107 · Cited by 198 · see citing works
Allostery and population shift in drug discovery
Kar, G., Keskin, Ö., Gürsoy, A., & Nussinov, R. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.09.002 · Cited by 190 · see citing works
Markwick, P. R. L., Bouvignies, G., & Blackledge, M. J. (2007) · Journal of the American Chemical Society · doi:10.1021/ja0687668 · Cited by 164 · see citing works
Kästner, J., Senn, H. M., Thiel, S., et al. (2006) · Journal of Chemical Theory and Computation · doi:10.1021/ct050252w · Cited by 162 · see citing works
Boehr, D. D., McElheny, D., Dyson, H. J., & Wright, P. E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914163107 · Cited by 142 · see citing works
Full correlation analysis of conformational protein dynamics
Lange, O. F., & Grubmüller, H. (2007) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21618 · Cited by 140 · see citing works
Targeting biomolecular flexibility with metadynamics
Leone, V., Marinelli, F., Carloni, P., & Parrinello, M. (2010) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2010.01.011 · Cited by 139 · see citing works
Accessing a Hidden Conformation of the Maltose Binding Protein Using Accelerated Molecular Dynamics
Bucher, D., Grant, B. J., Markwick, P. R. L., & McCammon, J. A. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002034 · Cited by 119 · see citing works
Furnham, N., Blundell, T. L., DePristo, M. A., et al. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb0306-184 · Cited by 119 · see citing works
Dynamics of a bacterial multidrug ABC transporter in the inward- and outward-facing conformations
Mehmood, S., Domene, C., Forest, É., & Jault, J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1204067109 · Cited by 112 · see citing works
Yang, S., Park, S., Makowski, L., et al. (2009) · Biophysical Journal · doi:10.1016/j.bpj.2009.03.036 · Cited by 110 · see citing works
Evolutionarily Conserved Linkage between Enzyme Fold, Flexibility, and Catalysis
Ramanathan, A., & Agarwal, P. K. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001193 · Cited by 106 · see citing works
Self-citationLoveridge, E. J., Behiry, E. M., Guo, J., et al. (2012) · Nature Chemistry · doi:10.1038/nchem.1296 · Cited by 92 · see citing works
Agarwal, P. K., Geist, A., & Gorin, A. A. (2004) · Biochemistry · doi:10.1021/bi0495228 · Cited by 88 · see citing works
Self-citationCamilloni, C., Robustelli, P., Simone, A. D., Cavalli, A., & Vendruscolo, M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja210951z · Cited by 84 · see citing works
Ordering a Dynamic Protein Via a Small-Molecule Stabilizer
Wang, N., Majmudar, C. Y., Pomerantz, W. C. K., Gagnon, J. K., Sadowsky, J., Meagher, J. L., Johnson, T. K., Stuckey, J. A., Brooks, C. L., Wells, J. A., et al. (2013) · Journal of the American Chemical Society · doi:10.1021/ja3122334 · Cited by 79 · see citing works
Fan, Y., Cembran, A., Ma, S.-H., & Gao, J.-L. (2013) · Biochemistry · doi:10.1021/bi301559q · Cited by 78 · see citing works
Discovering Conformational Sub-States Relevant to Protein Function
Ramanathan, A., Savol, A. J., LANGMEAD, C. J., Agarwal, P. K., & Chennubhotla, C. S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015827 · Cited by 72 · see citing works
Self-citationKinetics of Conformational Sampling in Ubiquitin
Ban, D., Funk, M., Gulich, R., Egger, D., Sabo, T. M., Walter, K. F. A., Fenwick, R. B., Giller, K., Pichierri, F., de Groot, B. L., et al. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201105086 · Cited by 71 · see citing works
Romo, T. D., Grossfield, A. M., & Pitman, M. C. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2009.09.046 · Cited by 67 · see citing works
Conformational dynamics and thermodynamics of protein–ligand binding studied by NMR relaxation
Akke, M. (2012) · Biochemical Society Transactions · doi:10.1042/bst20110750 · Cited by 62 · see citing works
Modulation of Calmodulin Plasticity by the Effect of Macromolecular Crowding
Homouz, D., Sanabria, H., Waxham, M. N., et al. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.06.073 · Cited by 58 · see citing works
How main-chains of proteins explore the free-energy landscape in native states
Senet, P., Maisuradze, G. G., Foulie, C., Delarue, P., & Scheraga, H. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810679105 · Cited by 57 · see citing works
Mincer, J. S., & Schwartz, S. D. (2004) · The Journal of Chemical Physics · doi:10.1063/1.1690239 · Cited by 55 · see citing works
Mechanism of Action of Cyclophilin A Explored by Metadynamics Simulations
Leone, V., Lattanzi, G., Molteni, C., & Carloni, P. (2009) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000309 · Cited by 47 · see citing works
Sinko, W., de Oliveira, C. A. F., Williams, S., Wynsberghe, A. W. V., Durrant, J. D., Cao, R., Oldfield, E., & McCammon, J. A. (2011) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2011.01101.x · Cited by 41 · see citing works
Engineering a Hyper-catalytic Enzyme by Photoactivated Conformation Modulation
Agarwal, P. K., Schultz, C., Kalivretenos, A. G., et al. (2012) · The Journal of Physical Chemistry Letters · doi:10.1021/jz201675m · Cited by 36 · see citing works
Self-citationThe Promoting Vibration in Human Heart Lactate Dehydrogenase Is a Preferred Vibrational Channel
Davarifar, A., Antoniou, D., & Schwartz, S. D. (2011) · The Journal of Physical Chemistry B · doi:10.1021/jp210347h · Cited by 34 · see citing works
Müller, M. M., Allison, J. R., Hongdilokkul, N., Gaillon, L., Kast, P., A, W. F. V. G., Marlière, P., & Hilvert, D. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003187 · Cited by 31 · see citing works
The importance of slow motions for protein functional loops
Skliros, A., Zimmermann, M. T., Chakraborty, D., Saraswathi, S., Katebi, A., Leelananda, S. P., Kloczkowski, A., & Jernigan, R. L. (2012) · Physical Biology · doi:10.1088/1478-3975/9/1/014001 · Cited by 30 · see citing works
Ramanathan, A., Savol, A. J., Agarwal, P. K., & Chennubhotla, C. S. (2012) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24135 · Cited by 28 · see citing works
Self-citationNeutron Scattering Reveals Enhanced Protein Dynamics in Concanavalin A Amyloid Fibrils.
Schirò, G., Vetri, V., Frick, B., Militello, V., Leone, M., & Cupane, A. (2012) · Journal of Physical Chemistry Letters · doi:10.1021/jz300082x · Cited by 23 · see citing works
QAARM: quasi-anharmonic autoregressive model reveals molecular recognition pathways in ubiquitin
Savol, A. J., Burger, V., Agarwal, P. K., et al. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr248 · Cited by 19 · see citing works
Self-citationRedox-Promoting Protein Motions in Rubredoxin
Borreguero, J. M., He, J., Meilleur, F., Weiss, K. L., Brown, C. M., Myles, D. A. A., Herwig, K. W., & Agarwal, P. K. (2011) · The Journal of Physical Chemistry B · doi:10.1021/jp201346x · Cited by 14 · see citing works
Self-citationBiomolecular simulations on petascale: promises and challenges
Agarwal, P. K., & Alam, S. R. (2006) · Journal of Physics Conference Series · doi:10.1088/1742-6596/46/1/046 · Cited by 12 · see citing works
Self-citation
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Research works printed but not linked: 2
- U. S. A. 2010, 107, 10890-10895.
- U. S. A. 2012, 109, 10832-10836.
Cited by
Sorted by citations
Wei, G., Xi, W., Nussinov, R., & Ma, B. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00562 · Cited by 436 · see citing works
The role of protein dynamics in the evolution of new enzyme function
Campbell, E., Kaltenbach, M., Correy, G. J., Carr, P. D., Porebski, B. T., Livingstone, E. K., Afriat-Jurnou, L., Buckle, A. M., Weik, M., Hollfelder, F., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2175 · Cited by 311 · see citing works
Skolnick, J., Gao, M., Zhou, H., & Singh, S. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c01114 · Cited by 251 · see citing works
Protein multiple conformations prediction using multi-objective evolution algorithm
Hou, M.-H., Jin, S.-R., Cui, X.-Y., Peng, C.-X., Zhao, K.-L., Song, L., & Zhang, G.-J. (2023) · doi:10.1101/2023.04.21.537776 · Cited by 29 · see citing works
- Authors
- Ramanathan, A., Savol, A., Burger, V., Chennubhotla, C. S., & Agarwal, P. K.
- Affiliations
- Oak Ridge National Laboratory (US)
- University of Pittsburgh (US)
- Corresponding author
- Chennubhotla, Chakra S.
- Agarwal, Pratul K.
- Venue
- Accounts of Chemical Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-08-29
- Volume
- 47
- Issue
- 1
- Pages
- 149-156
- ISSN
- 0001-4842 (ISSN-L)
- 1520-4898
- OpenAlex
- W2010931041
- Cited by
- 110
- References
- 54
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 5 · 2022: 13 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 9 · 2017: 9 · 2016: 13 · 2015: 8 · 2014: 4
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.osti.gov
- Locations
- Accounts of Chemical Research (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Oak Ridge National Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- protein conformational ensembles, conformational substates, conformational landscape, protein dynamics, protein function, enzyme catalysis, dihydrofolate reductase, cyclophilin A, allosteric modulation, photoactivation, enzyme engineering, drug design, structure-dynamics relationship
- MeSH terms
- Humans, Protein Conformation, Proteins, Computational Biology, Cyclophilin A, Biocatalysis
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