A second molecular biology revolution? The energy landscapes of biomolecular function
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Biomolecules are dynamical objects that are always interconverting between structures with varying energies, and this is the origin of allosteric mechanisms.
“biomolecules are dynamical objects that are always interconverting between a variety of structures with varying energies,166 and that this is the origin of allosteric mechanisms.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [166]
Biomolecules must be described statistically, not statically.
“Biomolecules must be described statistically, not statically.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [166]
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“For instance, establishment of preformed enzyme complexes for cell function has been proposed as a mechanism used by cells to rapidly respond to homeostasis unbalances [2,3], whereas pathways that regulate the conservation of protein folding have a key role [4].”
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“folding (23), an idea that suggests a unified view of protein folding that includes conformational transitions within the folded ensemble (32, 33).”
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“166,175 Static descriptions were the norm for decades.”
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“…complete understanding of equilibrium dynamics requires sampling both the structure space available and the underlying free-energy landscape (FEL; Frauenfelder et al., 1991; Zhuravlev and Papoian, 2010a; Nussinov and Wolynes, 2014; Röder et al., 2019) along its relevant dimensions ( Figures 1B,C ).”
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“[100] R.”
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“The shift of the ensemble can also explain the propagation of signaling, i.e., Ballo-networks^ (Nussinov et al. 2011; Szilagyi et al. 2013).”
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“com/oncotarget the complex dynamic circuitry, and population shifts in response to changing conditions, computational structural biology may foment and chart new territory [153].”
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“Macromolecules are not solid rocks; they are flexible, visiting multiple possible conformations (Nussinov and Wolynes 2014).”
BackgroundSelf-citationAllostery, and how to define and measure signal transduction
Nussinov, R., Tsai, C., & Jang, H. (2022) · Biophysical Chemistry · doi:10.1016/j.bpc.2022.106766 · Cited by 45 · see citing works
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“Proteins exist as dynamic ensembles of states [28]; not as rigid statues [29].”
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Self-citationInhibition of Nonfunctional Ras
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“Both types of proteins can be considered from the mechanistic free energy landscape standpoint, which epitomizes the ‘second molecular biological revolution’ (Nussinov and Wolynes, 2014).”
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Self-citationDistributions of experimental protein structures on coarse-grained free energy landscapes
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“functionally relevant ensembles of threedimensional conformation [5].”
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“effective potentials, free energy minimization, maximum entropy, computational mechanics, maximum calibre, motifs in biological networks, self-organization, compressed sensing, evolution as thermodynamics, algorithmic complexity and algorithmic laws of information [47,50–64].”
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Self-citationDrug resistance and tumor heterogeneity: cells and ensembles
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“Being unaware of this seminal work at the time, in 2014, Nussinov and Wolynes (2014) noted that even living things must conform to the laws of quantum mechanics and structural chemistry.”
Self-citationAn Energy Landscape Treatment of Decoy Selection in Template-Free Protein Structure Prediction
Akhter, N., Qiao, W., & Shehu, A. (2018) · Computation · doi:10.3390/computation6020039 · Cited by 15 · see citing works
“The energy landscape relates biologically-active conformations of a molecule to thermodynamic stability (and function) [22–25], and has been central to a better understanding of the relationship between protein structure, dynamics, and function [18,26].”
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Self-citationBivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B 12 repair
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“…selection/population shift principle (Boehr et al., 2009) that has been reported to regulate the structure-function relationship in proteins (Nussinov and Wolynes, 2014), mutations change the probability (which is related to their energetics) with which structures are populated at…”
Unsupervised and Supervised Learning over the Energy Landscape for Protein Decoy Selection
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“The energy landscape exposes the relationship between molecular structure, changes to structure, and biological activity or function [5].”
BackgroundFrom mutations to mechanisms and dysfunction via computation and mining of protein energy landscapes
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Mechanical Unfolding Response of Proteins
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Physics-Grounded Evaluation to Guide Accurate Biomolecular PredictionPreprint
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“Moreover, ensemble generation is a rapidly growing frontier of predictive models 47–50 , an important direction as ensembles provide the states and probabilities that are ultimately needed to provide quantitative prediction of function 51–53 (Fig.”
How residence time works in allosteric drugs
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Energy landscapes in molecular biology: History, principles, and perspectives
Nussinov, R., Regev, C., & Jang, H. (2026) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583526100134 · Cited by 8 · see citing works
“The landscape concept has not only brought forth new theoretical interpretive tools, and inspired new experimental approaches, but bore clinical fruit (Nussinov and Wolynes, 2014), leading to next-generation drug discovery (Nussinov et al. , 2025c).”
InfluentialSelf-citationUsing subpopulation EAs to map molecular structure landscapes
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“Deep and narrow minima constitute structural states with few but very low-energy structures, whereas shallow and broad minima constitute (more heterogeneous) states with many but not as low-energy structures [25].”
BackgroundUsing Sequence-Predicted Contacts to Guide Template-free Protein Structure Prediction
Zaman, A. B., Parthasarathy, P. V., & Shehu, A. (2019) · ACM International Conference on Bioinformatics, Computational Biology, and Health Informatics (ACM-BCB) · doi:10.1145/3307339.3342175 · Cited by 7 · see citing works
“…under physical principles demonstrated in theory and experiment that the three-dimensional/tertiary structures comprising the stable, long-time populated state(s) observed in the wet laboratory [2] reside in deep and broad basins of the potential energy function summing up atomic interactions [15].”
BackgroundOn the Relationship Between Protein Stability, Thermostability, and Allosteric Signaling
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From Pathogens to Cancer: Are Cancer Cells Evolved Mitochondrial Super Cells?
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Probing biological mechanisms with chemical tools
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Self-citationWeight average approaches for predicting dynamical properties of biomolecules
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Decoy selection for protein structure prediction via extreme gradient boosting and ranking
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“features an ensemble of structural states near or far from the native state and an extensive collection of intermediate states that shape the multi-modal and multi-dimensional nature of the landscape [45]. The concept of a basin is connected to a local/focal minimum. A focal minimum in a landscape is surrounded by a b…”
BackgroundAllosteric Changes in the Conformational Landscape of Src Kinase upon Substrate Binding.
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First-passage times in complex energy landscapes: a case study with nonmuscle myosin II assembly
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“examples from chemistry and condensed matter physics include chemical kinetics [2, 3] or glass-forming systems [4–6], in a biophysical context, energy landscapes are central for explaining a wide range of biomolecular processes [7].”
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How do mutations and allosteric inhibitors modulate caspase-7 activity? A molecular dynamics study
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“Allosteric modulation can be observed when binding of a small molecule/ligand to a specific site affects the properties of a distant site in the protein (Greener & Sternberg, 2018; Guo & Zhou, 2016; Liu & Nussinov, 2016; Nussinov & Wolynes, 2014).”
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Reconstruction and Decomposition of High-Dimensional Landscapes via Unsupervised Learning
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“In particular, the energy landscape has improved our understanding of the relationship between protein structure, structure plasticity, and function [7, 23].”
BackgroundTandem Domains with Tuned Interactions Are a Powerful Biological Design Principle
Nussinov, R., & Tsai, C. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002306 · Cited by 3 · see citing works
“Structures are not rocks; and the only way to gain insight is to consider molecules as ensembles of multiple interconverting conformations, where the relative population of a certain conformation, or “state”, is dynamic [3].”
BackgroundSelf-citationEnergy Landscapes in Chemical Reactions and Transport
Weitzel, K. (2025) · ChemPhysChem · doi:10.1002/cphc.202400877 · Cited by 2 · see citing works
Protein aggregation in health and disease: A looking glass of two faces
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“Proteins switch between dierent shapes/structures to interact with dierent molecular partners [15].”
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“Enzyme catalysis is a structurally dynamic process consisting of multiple steps including substrate binding, transition state stabilization, and product release (1-4).”
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Robust SH2 binding affinity indicates minimal SH3-to-SH2 communication in Grb2
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Reconstructing and mining protein energy landscape to understand disease
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“Obtaining detailed representations of protein energy landscapes is central to elucidating the structural dynamics that regulates protein function or dysfunction [2].”
BackgroundElucidating the Role of Wildtype and Variant FGFR2 Structural Dynamics in (Dys)Function and Disorder
Lian, Y., Bodian, D. L., & Shehu, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25084523 · Cited by 1 · see citing works
“By relying on the principle of conformation selection [27,28], we harness the structural diversity present among PDB-deposited tertiary structures of wildtype and variant forms of FGFR2 in various functional states.”
BackgroundKang, H.-S., & Sattler, M. (2018) · Emerging Topics in Life Sciences · doi:10.1042/etls20170090 · Cited by 1 · see citing works
Akhter, N., Lei, J., Qiao, W., et al. (2018) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm.2018.8621411 · Cited by 1 · see citing works
“their proximity and energetics [4].”
Antigen Binding Reshapes Antibody Energy Landscape and Conformation Dynamics
Kabir, K. L., Nussinov, R., Ma, B., & Shehu, A. (2021) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm52615.2021.9669830 · Cited by 1 · see citing works
Self-citationGolf-course and funnel energy landscapes: Protein folding concepts in martensites
Shankaraiah, N. (2017) · Physical review. E · doi:10.1103/physreve.95.063003
Frehse, G., & Althoff, M. (2017) · Institute of Science and Technology Austria
Out of one, many: Exploiting intrinsic motions to explore protein structure spaces
Morris, D., Maximova, T., Plaku, B., et al. (2017) · IEEE International Conference on Computational Advances in Bio and Medical Sciences · doi:10.1109/iccabs.2017.8114290
“In principle, these issues can be addressed via a detailed reconstruction of the energy landscape in silico [2].”
BackgroundAttenuating dependence on structural data in computing protein energy landscapes
Morris, D., Maximova, T., Plaku, E., et al. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-2822-5
Discovering Differences and Similarities among Species Based on Numeric Features of microRNAsPreprint
Zhu, R., Zhang, Z., Xin, D., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/767046
“Almost all kinds of biology functional molecular have specific nucleotide composition or special molecular structure 39, 40, 41,42,43,44 .”
Background
- Authors
- Nussinov, R., & Wolynes, P. G.
- Affiliations
- Tel Aviv University (IL)
- Center for Theoretical Biological Physics (US)
- Venue
- Physical Chemistry Chemical Physics
- Publisher
- Royal Society of Chemistry (RSC)
- Published
- 2014
- Volume
- 16
- Issue
- 14
- Pages
- 6321
- ISSN
- 1463-9076 (ISSN-L)
- 1463-9084
- OpenAlex
- W2165550831
- Cited by
- 104
- References
- 0
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 21 · 2018: 10 · 2017: 13 · 2016: 9 · 2015: 6 · 2014: 1
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physical Chemistry Chemical Physics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- energy landscape, biomolecular function, molecular biology, protein folding, conformational change
- MeSH terms
- DNA, Models, Molecular, Proteins, Quantum Theory, Thermodynamics
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