Quantifying the topography of the intrinsic energy landscape of flexible biomolecular recognition
Open accessAbstract
Significance: Biomolecular binding, which controls the realization of biomolecular function, is ubiquitous and fundamental to many cellular processes. We quantified the intrinsic energy landscapes of flexible biomolecular recognition—i.e., the binding–folding. Our findings reveal that the energy landscape topography determines the thermodynamics, kinetics, and the association mechanism of the binding–folding dynamics. These three aspects are closely related to feasibility, efficiency, and the ways of realizing biomolecular function, respectively. Our results provide a unique way to address the long-standing debate of the “structure–dynamics–function” relationship using landscape topography and establish the connections between recognition landscape theory and experimental measurements.
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?
Recognition mechanisms are governed by the shape of the intrinsic energy landscape.
“The recognition mechanism depends on the topography of the intrinsic energy landscape.”
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 [158]
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
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1992) · Springer series in statistics · doi:10.1007/978-1-4612-4380-9_25 · Cited by 45,232 · see citing works
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1958) · Journal of the American Statistical Association · doi:10.1080/01621459.1958.10501452 · Cited by 39,158 · see citing works
THE weighted histogram analysis method for free‐energy calculations on biomolecules. I. The method
Kumar, S., Rosenberg, J. M., Bouzida, D., Swendsen, R. H., & Kollman, P. A. (1992) · Journal of Computational Chemistry · doi:10.1002/jcc.540130812 · Cited by 6,808 · see citing works
Replica-exchange molecular dynamics method for protein folding
Sugita, Y., & Okamoto, Y. (1999) · Chemical Physics Letters · doi:10.1016/s0009-2614(99)01123-9 · Cited by 4,499 · see citing works
Intrinsically unstructured proteins and their functions
Dyson, H. J., & Wright, P. E. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1589 · Cited by 3,871 · see citing works
The Energy Landscapes and Motions of Proteins
Frauenfelder, H., Sligar, S. G., & Wolynes, P. G. (1991) · Science · doi:10.1126/science.1749933 · Cited by 3,250 · see citing works
Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm
Wright, P. E., & Dyson, H. J. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3110 · Cited by 2,968 · see citing works
Funnels, pathways, and the energy landscape of protein folding: A synthesis
Bryngelson, J. D., Onuchic, J. N., Socci, N. D., & Wolynes, P. G. (1995) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.340210302 · Cited by 2,648 · see citing works
From Levinthal to pathways to funnels
Dill, K. A., & Chan, H. S. (1997) · Nature Structural & Molecular Biology · doi:10.1038/nsb0197-10 · Cited by 2,293 · see citing works
Intrinsically disordered protein
Dunker, A. K., Lawson, J. D., Brown, C. J., Williams, R. M., Romero, P., Oh, J. S., Oldfield, C. J., Campen, A. M., Ratliff, C. M., Hipps, K. W., et al. (2001) · Journal of Molecular Graphics and Modelling · doi:10.1016/s1093-3263(00)00138-8 · Cited by 2,272 · see citing works
THEORY OF PROTEIN FOLDING: The Energy Landscape Perspective
Onuchic, J. N., Luthey-Schulten, Z., & Wolynes, P. G. (1997) · Annual Review of Physical Chemistry · doi:10.1146/annurev.physchem.48.1.545 · Cited by 2,210 · 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
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
Natively unfolded proteins: A point where biology waits for physics
Uversky, V. N. (2002) · Protein Science · doi:10.1110/ps.4210102 · Cited by 1,815 · see citing works
Spin glasses and the statistical mechanics of protein folding.
Bryngelson, J. D., & Wolynes, P. G. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.21.7524 · Cited by 1,647 · see citing works
Intrinsically Disordered Proteins
Uversky, V. N. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-374984-0.01698-3 · Cited by 1,646 · see citing works
Dynamics of ligand binding to myoglobin
Austin, R. H., Beeson, K. W., Eisenstein, L., Frauenfelder, H., & GUNSALUS, I. C. (1975) · Biochemistry · doi:10.1021/bi00695a021 · Cited by 1,626 · see citing works
Random-energy model: An exactly solvable model of disordered systems
Derrida, B. (1981) · Physical review. B, Condensed matter · doi:10.1103/physrevb.24.2613 · Cited by 1,363 · see citing works
Onuchic, J. N., & Wolynes, P. G. (2004) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2004.01.009 · Cited by 1,298 · see citing works
Wolynes, P., Onuchic, J., & Thirumalai, D. (1995) · Science · doi:10.1126/science.7886447 · Cited by 1,080 · see citing works
Wright, P. E., & Dyson, H. J. (2009) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2008.12.003 · Cited by 1,012 · see citing works
Speeding molecular recognition by using the folding funnel: The fly-casting mechanism
Shoemaker, B. A., Portman, J. J., & Wolynes, P. G. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.160259697 · Cited by 971 · see citing works
Protein folding funnels: a kinetic approach to the sequence-structure relationship.
Leopold, P., Montal, M., & Onuchic, J. N. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.18.8721 · Cited by 929 · see citing works
Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling
Uversky, V. N., Oldfield, C. J., & Dunker, A. K. (2005) · Journal of Molecular Recognition · doi:10.1002/jmr.747 · Cited by 847 · see citing works
Intermediates and barrier crossing in a random energy model (with applications to protein folding)
Bryngelson, J. D., & Wolynes, P. G. (1989) · The Journal of Physical Chemistry · doi:10.1021/j100356a007 · Cited by 746 · see citing works
Intrinsic Disorder and Functional Proteomics
Predrag Radivojac, A., Iakoucheva, L. M., Oldfield, C. J., Zoran Obradovic, A., Uversky, V. N., & Dunker, A. K. (2006) · Biophysical Journal · doi:10.1529/biophysj.106.094045 · Cited by 705 · see citing works
Folding funnels, binding funnels, and protein function
Tsai, C., Kumar, S., Ma, B., & Nussinov, R. (1999) · Protein Science · doi:10.1110/ps.8.6.1181 · Cited by 648 · see citing works
Folding and binding cascades: Dynamic landscapes and population shifts
Kumar, S., Ma, B., Tsai, C., Sinha, N., & Nussinov, R. (2000) · Protein Science · doi:10.1110/ps.9.1.10 · Cited by 595 · see citing works
Connections between some kinetic and equilibrium theories of the glass transition
Kirkpatrick, T. R., & Wolynes, P. G. (1987) · Physical Review A · doi:10.1103/physreva.35.3072 · Cited by 556 · see citing works
Net charge per residue modulates conformational ensembles of intrinsically disordered proteins
Mao, A. H., Crick, S. L., Vitalis, A., Chicoine, C. L., & Pappu, R. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911107107 · Cited by 554 · see citing works
Toward an outline of the topography of a realistic protein-folding funnel.
Onuchic, J. N., Wolynes, P. G., Luthey-Schulten, Z., & Socci, N. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.8.3626 · Cited by 523 · see citing works
Engineering of stable and fast-folding sequences of model proteins.
Shakhnovich, E. I., & Gutin, A. M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.15.7195 · Cited by 516 · see citing works
Charge interactions can dominate the dimensions of intrinsically disordered proteins
Müller-Späth, S., Soranno, A., Hirschfeld, V., Hofmann, H., Rüegger, S., Reymond, L., Nettels, D., & Schuler, B. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001743107 · Cited by 491 · see citing works
Stable and metastable states in mean-field Potts and structural glasses
Kirkpatrick, T. R., & Wolynes, P. G. (1987) · Physical review. B, Condensed matter · doi:10.1103/physrevb.36.8552 · Cited by 485 · see citing works
Veitshans, T., Klimov, D., & Thirumalai, D. (1997) · Folding and Design · doi:10.1016/s1359-0278(97)00002-3 · Cited by 397 · see citing works
Iben, I. E. T., Braunstein, D., Doster, W., Frauenfelder, H., Hong, M., Johnson, J. B., Luck, S., Ormos, P., Schulte, A., Steinbach, P. J., et al. (1989) · Physical Review Letters · doi:10.1103/physrevlett.62.1916 · Cited by 396 · see citing works
Protein topology determines binding mechanism
Levy, Y., Wolynes, P. G., & Onuchic, J. N. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2534828100 · Cited by 324 · see citing works
SMOG@ctbp: simplified deployment of structure-based models in GROMACS
Noel, J. K., Whitford, P. C., Sanbonmatsu, K. Y., & Onuchic, J. N. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq498 · Cited by 296 · see citing works
The experimental survey of protein-folding energy landscapes
Oliveberg, M., & Wolynes, P. G. (2005) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583506004185 · Cited by 275 · see citing works
Conformational stability of dimeric proteins: Quantitative studies by equilibrium denaturation
Neet, K., & Timm, D. E. (1994) · Protein Science · doi:10.1002/pro.5560031202 · Cited by 252 · see citing works
Xu, J., Baase, W. A., Baldwin, E. P., & Matthews, B. W. (1998) · Protein Science · doi:10.1002/pro.5560070117 · Cited by 229 · see citing works
Folding funnels and energy landscapes of larger proteins within the capillarity approximation
Wolynes, P. G. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.12.6170 · Cited by 218 · see citing works
Levy, Y., Cho, S. S., Onuchic, J. N., & Wolynes, P. G. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.12.021 · Cited by 213 · see citing works
Understanding protein folding with energy landscape theory Part I: Basic concepts
Plotkin, S. S., & Onuchic, J. N. (2002) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583502003761 · Cited by 199 · see citing works
Molecular Recognition by Induced Fit: How Fit is the Concept?
Bosshard, H. R. (2001) · Physiology · doi:10.1152/physiologyonline.2001.16.4.171 · Cited by 184 · see citing works
Brooks, C. L., Onuchic, J. N., & Wales, D. J. (2001) · Science · doi:10.1126/science.1062559 · Cited by 180 · see citing works
Gunasekaran, K., Tsai, C., & Nussinov, R. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.07.002 · Cited by 177 · see citing works
How, when and why proteins collapse: the relation to folding
Haran, G. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.10.005 · Cited by 160 · see citing works
Charge Interactions Can Dominate the Dimensions of Intrinsically Disordered Proteins
Soranno, A., Müller-Späth, S., Hirschfeld, V., Hofmann, H., Rüegger, S., Reymond, L., Nettels, D., & Schuler, B. (2011) · Biophysical Journal · doi:10.1016/j.bpj.2010.12.278 · Cited by 160 · see citing works
Energy Landscape Theory, Funnels, Specificity, and Optimal Criterion of Biomolecular Binding
Wang, J., & Verkhivker, G. M. (2003) · Physical Review Letters · doi:10.1103/physrevlett.90.188101 · Cited by 158 · see citing works
Self-citationStatistical mechanics of a correlated energy landscape model for protein folding funnels
Plotkin, S. S., Wang, J., & Wolynes, P. G. (1997) · The Journal of Chemical Physics · doi:10.1063/1.473355 · Cited by 147 · see citing works
Self-citationDynamics of different functional parts of bacteriorhodopsin: H- 2 H labeling and neutron scattering
Réat, V., Patzelt, H., Ferrand, M., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4970 · Cited by 142 · see citing works
Recent successes of the energy landscape theory of protein folding and function
Wolynes, P. G. (2005) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583505004075 · Cited by 136 · see citing works
The physics and bioinformatics of binding and folding—an energy landscape perspective
Papoian, G. A., & Wolynes, P. G. (2003) · Biopolymers · doi:10.1002/bip.10286 · Cited by 124 · see citing works
Conformational stability and folding mechanisms of dimeric proteins
Rumfeldt, J., Galvagnion, C., Vassall, K. A., & Meiering, E. M. (2008) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2008.05.004 · Cited by 122 · see citing works
Predictive energy landscapes for protein–protein association
Zheng, W., Schafer, N. P., Davtyan, A., Papoian, G. A., & Wolynes, P. G. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1216215109 · Cited by 110 · see citing works
Mechanism and evolution of protein dimerization
Nussinov, R., Xu, D., & Tsai, C. (1998) · Protein Science · doi:10.1002/pro.5560070301 · Cited by 107 · see citing works
Das, P., Matysiak, S., & Clementi, C. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409471102 · Cited by 100 · see citing works
Fast-folding eriments and the topography of protein folding energy landscapes
Wolynes, P. G., Luthey-Schulten, Z. A., & Onuchic, J. N. (1996) · Chemistry & Biology · doi:10.1016/s1074-5521(96)90090-3 · Cited by 98 · see citing works
Kinetic partitioning mechanism as a unifying theme in the folding of biomolecules
Thirumalai, D., Klimov, D. K., & Woodson, S. A. (1997) · Theoretical Chemistry Accounts · doi:10.1007/s002140050198 · Cited by 93 · see citing works
Capillarity theory for the fly-casting mechanism
Trizac, E., Levy, Y., & Wolynes, P. G. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914727107 · Cited by 82 · see citing works
Wang, J., Onuchic, J. N., & Wolynes, P. G. (1996) · Physical Review Letters · doi:10.1103/physrevlett.76.4861 · Cited by 80 · see citing works
Self-citationTopography of funneled landscapes determines the thermodynamics and kinetics of protein folding
Wang, J., de Oliveira, R. J., Chu, X., Whitford, P. C., Chahine, J., Han, W., Wang, E., Onuchic, J. N., & Leite, V. B. P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1212842109 · Cited by 76 · see citing works
Self-citationQuantifying biological specificity: The statistical mechanics of molecular recognition
Janin, J. (1996) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.4 · Cited by 74 · see citing works
Chu, X., Wang, Y., Gan, L., Bai, Y., Han, W., Wang, E., & Wang, J. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002608 · Cited by 73 · see citing works
Self-citationWang, J., Wang, Y., Chu, X., Hagen, S. J., Han, W., & Wang, E. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1001118 · Cited by 72 · see citing works
Self-citationFrom protein folding to protein function and biomolecular binding by energy landscape theory
Schug, A. H., & Onuchic, J. N. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.09.012 · Cited by 66 · see citing works
The roles of residues Tyr150, Glu272, and His314 in class C β-lactamases
Dubus, A., Ledent, P., Lamotte‐Brasseur, J., & Frère, J. (1996) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(199608)25:4 · Cited by 62 · see citing works
Electrostatic effects on funneled landscapes and structural diversity in denatured protein ensembles
Weinkam, P., Pletneva, E. V., Gray, H. B., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813120106 · Cited by 54 · see citing works
Quantifying Intrinsic Specificity: A Potential Complement to Affinity in Drug Screening
Wang, J., Zheng, X., Yang, Y., Drueckhammer, D. G., Yang, W. Y., Verkhivker, G. M., & Wang, E. (2007) · Physical Review Letters · doi:10.1103/physrevlett.99.198101 · Cited by 49 · see citing works
Self-citationReddy, G. B., Bharadwaj, S., & Surolia, A. (1999) · Biochemistry · doi:10.1021/bi982828s · Cited by 45 · see citing works
Wang, Y., Chu, X., Suo, Z., Wang, E., & Wang, J. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3045663 · Cited by 37 · see citing works
Self-citationStatistics, pathways and dynamics of single molecule protein folding
Wang, J. (2002) · The Journal of Chemical Physics · doi:10.1063/1.1527633 · Cited by 29 · see citing works
Self-citationOptimal Specificity and Function for Flexible Biomolecular Recognition
Wang, J., Xu, L., & Wang, E. (2007) · Biophysical Journal · doi:10.1529/biophysj.107.105551 · Cited by 24 · see citing works
Self-citationKohn, J. E., Gillespie, B., & Plaxco, K. W. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.09.005 · Cited by 16 · see citing works
Diffusion and single molecule dynamics on biomolecular interface binding energy landscape
Wang, J. (2005) · Chemical Physics Letters · doi:10.1016/j.cplett.2005.11.016 · Cited by 14 · see citing works
Self-citationThe cooperative nature of hydrophobic forces and protein folding kinetics
Wang, J., Lee, C.-L., & Stell, G. R. (2005) · Chemical Physics · doi:10.1016/j.chemphys.2005.04.045 · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Levinthal C (1969) Proceedings in Mossbauer Spectroscopy in Biological Systems, eds Debrunner P, Tsibris J, Munck E (Univ of Illinois Press, Urbana, IL), pp 22-24.
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
Protein-Protein Docking: From Interaction to Interactome
Vakser, I. A. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2014.08.033 · Cited by 318 · see citing works
Efficient flexible backbone protein-protein docking for challenging targets
Marze, N. A., Roy Burman, S. S., Sheffler, W., & Gray, J. J. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty355 · Cited by 173 · see citing works
- Authors
- Chu, X., Gan, L., Wang, E., & Wang, J.
- Affiliations
- Jilin University (CN)
- Chinese Academy of Sciences (CN)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-06-10
- Volume
- 110
- Issue
- 26
- Pages
- E2342-51
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3696809
- OpenAlex
- W2011246315
- Cited by
- 62
- References
- 77
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 9 · 2016: 5 · 2015: 5 · 2014: 8 · 2013: 3
- FWCI
- 3.13
- 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 Natural Science Foundation of China
- 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 › RNA and protein synthesis mechanisms
- Keywords
- biomolecular recognition, homodimer, density of states, landscape roughness, configurational entropy, binding kinetics, trapping temperature, temperature-dependent kinetics, structure-based models
- MeSH terms
- Computer Simulation, Kinetics, Models, Molecular, Protein Binding, Proteins, Thermodynamics, Protein Folding, Protein Structure, Quaternary, Protein Multimerization, 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
