A quantitative measure for protein conformational heterogeneity
Open accessAbstract
Conformational heterogeneity is a defining characteristic of proteins. Intrinsically disordered proteins (IDPs) and denatured state ensembles are extreme manifestations of this heterogeneity. Inferences regarding globule versus coil formation can be drawn from analysis of polymeric properties such as average size, shape, and density fluctuations. Here we introduce a new parameter to quantify the degree of conformational heterogeneity within an ensemble to complement polymeric descriptors. The design of this parameter is guided by the need to distinguish between systems that couple their unfolding-folding transitions with coil-to-globule transitions and those systems that undergo coil-to-globule transitions with no evidence of acquiring a homogeneous ensemble of conformations upon collapse. The approach is as follows: Each conformation in an ensemble is converted into a conformational vector where the elements are inter-residue distances. Similarity between pairs of conformations is quantified using the projection between the corresponding conformational vectors. An ensemble of conformations yields a distribution of pairwise projections, which is converted into a distribution of pairwise conformational dissimilarities. The first moment of this dissimilarity distribution is normalized against the first moment of the distribution obtained by comparing conformations from the ensemble of interest to conformations drawn from a Flory random coil model. The latter sets an upper bound on conformational heterogeneity thus ensuring that the proposed measure for intra-ensemble heterogeneity is properly calibrated and can be used to compare ensembles for different sequences and across different temperatures. The new measure of conformational heterogeneity will be useful in quantitative studies of coupled folding and binding of IDPs and in de novo sequence design efforts that are geared toward controlling the degree of heterogeneity in unbound forms of IDPs.
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The breadth of conformational distributions varies among proteins, with some showing lower and some higher structural variability as measured by RMSD and other parameters.
“The breath of the distributions of the ensembles varies across proteins; some with lower and some with higher structural variability as measured by root-mean-square deviation (RMSD) and other parameters2.”
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 [2]
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“Here, xFRC is the value we obtain from our numerical approximation of the Flory random coil (FRC), which is an ideal chain model where all non-nearest neighbor interactions are ignored (2, 62).”
BackgroundMethodSelf-citationSequence-to-conformation relationships of disordered regions tethered to folded domains of proteins
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“Previous experiments and simulations have suggested that polyQ prefers to adopt an array of collapsed conformations of equivalent thermodynamic preference [22, 27, 28] that arises from water being a poor solvent for polyQ [29].”
BackgroundSelf-citationFlexibility Coexists with Shape-Persistence in Cyanostar Macrocycles
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“It seems plausible that unfolded states characterized by amplitudes of and correlations among conformational fluctuations that are reminiscent of polymers in theta states may facilitate the search for the folded state more effectively than an expanded self-avoiding random walk or compact globular ensemble that hinders…”
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Molecular grammars of predicted intrinsically disordered regions that span the human proteome
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Self-citationSalt-Induced Transitions in the Conformational Ensembles of Intrinsically Disordered Proteins
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Studies of protein folding and dynamics using single molecule fluorescence spectroscopy
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Self-citationA Coarse-Grained Model for Polyglutamine Aggregation Modulated by Amphipathic Flanking Sequences
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“Importantly, disorder refers to measures that quantify the multi-parameter, sequence-specific conformational distributions that reflect the interplay of chainsolvent and intra-chain interactions (Lyle et al., 2013).”
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Nuclear speckle proteins form intrinsic and MALAT1-dependent microphases
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Glycine in Water Favors the Polyproline II State
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Perspective: Reaches of chemical physics in biology
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Physical basis of the disorder-order transition
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IDPs and IDRs in biomolecular condensates
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Short tandem repeats bind transcription factors to tune eukaryotic gene expressionPreprint
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Drug resistance and tumor heterogeneity: cells and ensembles
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“The conformational distributions are determined by statistical thermodynamics (Frauenfelder et al. 1991; Lyle et al. 2013), and the heights of the free energy barriers sepa-rating them define the conformational exchange rates.”
Expanding the Range of Protein Function at the Far End of the Order-Structure Continuum
Burger, V., Nolasco, D. O., & Stultz, C. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.692590 · Cited by 16 · see citing works
“Although the axes in this continuum are qualitative, quantitative metrics have been proposed to quantify ensemble heterogeneity, either using atomistic representations for the structural ensemble (3, 18), or from a topological analysis of the energy surface (19).”
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“Instead, they are defined by a heterogeneous ensemble of conformations [2].”
Investigating the ferric ion binding site of magnetite biomineralisation protein Mms6
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“e) Global heterogeneity quantifies the extent of conformational disorder in terms of the distribution of structurally dissimilar conformations [49].”
BackgroundDynamics of the BH3-Only Protein Binding Interface of Bcl-xL
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“Intensive efforts have been focused on characterizing the conformational properties of unbound IDPs and understanding how these properties may support facile and robust binding to specific targets (9,10).”
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Toward a unified framework for determining conformational ensembles of disordered proteins
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Intrinsically Disordered Proteins as Drug Targets
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“Small Angle X-ray Scattering [47,48] or singlemolecule fluorescence [28,49,51] as well as employing atomistic and coarse-grained simulations [20,52-55].”
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“These structural deviations vary over time, some proteins experience lower deviations and some with higher variability which can be measured by the root-meansquare deviation (RMSD), and other parameters such as the root-mean-square fluctuation (RMSF), and the radius of gyration (ROG) (Lyle et al. 2013).”
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“…frameworks introduced here, combined with human (cid:0) interpretable ensemble definitions, can be extended to other protein subclasses—such as GPCRs, tumor necrosis factors (TNFs), intrinsically disordered proteins (IDPs) 56 —where conformational heterogeneity drives molecular recognition 57 .”
Modeling intrinsically disordered regions from AlphaFold2 to AlphaFold3
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“Unlike globular proteins that adopt a well-defined tertiary structure, intrinsically disordered proteins and regions (IDRs hereafter) exist as a dynamic ensemble of conformations (Lyle et al., 2013).”
Intrinsically disordered regions: a platform for regulated assembly of biomolecular condensates
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Uncovering non-random binary patterns within sequences of intrinsically disordered proteinsPreprint
Cohan, M. C., Shinn, M. K., Lalmansingh, J. M., & Pappu, R. V. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.19.456831 · Cited by 7 · see citing works
“Accordingly, we conclude that despite their importance as descriptors of sequence-ensemble-function relationships 14,17,28,34,35,37-39,43 , the parameters introduced to quantify mixing vs. segregation of different types of amino acids within IDRs cannot be deployed to compare patterns across…”
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Advances in the determination of disordered protein ensemble
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Compositional control of ageing kinetics in TDP-43 condensatesPreprint
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Disentangling Folding from Energetic Traps in Simulations of Disordered Proteins
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Sequence Length Controls Coil-to-Globule Transition in Elastin-like Polypeptides
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Local and Global Behavior of Unfolded and Intrinsically Disordered Peptides and Proteins
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Structural Features of a Tiny Viral Protein, ORF7b of SARS-CoV-2
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“Note: We evaluated the protein’s charge distribution using the methods of Das and Pappu [41,42], calculating the fraction of charged residues (FCR) as FCR = |f+ + f − | and the net charge per residue (NCPR) as |f+ − f − |.”
Structural Heterogeneity and Dynamics of the Unfolded Ensemble
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“We refer to this combination of requirements as a “Goldilocks precept” for the evolution of sequence features within IDPs / IDRs.”
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Disentangling the Protein Order/Disorder Continuum Using a Sequence-Based Foldability ScorePreprint
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- Authors
- Lyle, N., Das, R. K., & Pappu, R. V.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- The Journal of Chemical Physics
- Publisher
- AIP Publishing
- Published
- 2013-07-11
- Volume
- 139
- Issue
- 12
- Pages
- 121907-121907
- ISSN
- 0021-9606 (ISSN-L)
- 1089-7690
- PMC
- PMC3724800
- OpenAlex
- W1997915717
- Cited by
- 85
- References
- 89
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 2 · 2023: 2 · 2022: 13 · 2021: 10 · 2020: 8 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 1
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Chemical Physics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (1121867)
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS056114)
- 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
- protein conformational heterogeneity, intrinsically disordered proteins, coil-globule transition, coupled folding and binding, protein folding
- MeSH terms
- Monte Carlo Method, Peptides, Protein Conformation, Proteins, Thermodynamics, Protein Folding, Molecular Dynamics Simulation
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