CoChat
Sign Up
PreprintCited by 134Protein Structure and DynamicsAdvanced Physical and Chemical Molecular InteractionsRNA and protein synthesis mechanisms

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

A coarse-grained model for disordered and multi-domain proteins

Open access
Cao, Fan, von Bülow, Sören, Tesei, Giulio, Lindorff-Larsen, Kresten·2024·Protein Science
DOI 10.1101/2024.02.03.578735PMC PMC11481261

Preprint — published as 10.1002/pro.5172 · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

Many proteins contain more than one folded domain, and such modular multi-domain proteins help expand the functional repertoire of proteins. Because of their larger size and often substantial dynamics, it may be difficult to characterize the conformational ensembles of multi-domain proteins by simulations. Here, we present a coarse-grained model for multi-domain proteins that is both fast and provides an accurate description of the global conformational properties in solution. We show that the accuracy of a one-bead-per-residue coarse-grained model depends on how the interaction sites in the folded domains are represented. Specifically, we find excessive domain-domain interactions if the interaction sites are located at the position of the C α atoms. We also show that if the interaction sites are located at the centre of mass of the residue, we obtain good agreement between simulations and experiments across a wide range of proteins. We then optimize our previously described CALVADOS model using this centre-of-mass representation, and validate the resulting model using independent data. Finally, we use our revised model to simulate phase separation of both disordered and multi-domain proteins, and to examine how the stability of folded domains may differ between the dilute and dense phases. Our results provide a starting point for understanding interactions between folded and disordered regions in proteins, and how these regions affect the propensity of proteins to self-associate and undergo phase separation.

Overview

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2024.02.03.578735

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

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.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Show all 1 references

Research works printed but not linked: 125

  1. 2021, Refinement of a-synuclein ensembles against SAXS data: Comparison of force fields and methods, Frontiers in molecular biosciences, 8, 654333, 10.3389/fmolb.2021.654333 · DOI
  2. 10.1101/2024.04.29.591724 · DOI
  3. 10.1021/ja01163a006 · DOI
  4. Alshareedah I , Borcherds W , Cohen S , Farag M , Singh A , Bremer A , Pappu R , Mittag T , Banerjee P. Sequence-specific interactions determine viscoelastic moduli and aging dynamics of protein condensates.. 2023;. · DOI
  5. 2021, An integrative structural biology analysis of von Willebrand factor binding and processing by ADAMTS-13 in solution, Journal of Molecular Biology, 433, 166954, 10.1016/j.jmb.2021.166954 · DOI
  6. 2019, Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome, Nature communications, 10, 3967, 10.1038/s41467-019-11951-x · DOI
  7. 10.1021/ja802124e · DOI
  8. 2020, Simulation of FUS protein condensates with an adapted coarse-grained model, Journal of Chemical Theory and Computation, 17, 525
  9. 2009, Generic coarse-grained model for protein folding and aggregation, The Journal of chemical physics, 130, 06B621
  10. 10.1074/jbc.M210857200 · DOI
  11. 2021, On the roles of intrinsically disordered proteins and regions in cell communication and signaling, Cell Communication and Signaling, 19, 88, 10.1186/s12964-021-00774-3 · DOI
  12. 2023, Pragmatic Coarse-Graining of Proteins: Models and Applications, Journal of Chemical Theory and Computation, 19, 7112, 10.1021/acs.jctc.3c00733 · DOI
  13. 10.1073/pnas.2003773117 · DOI
  14. 10.1073/pnas.1706197114 · DOI
  15. 2022, Deciphering how naturally occurring sequence features impact the phase behaviours of disordered prion-like domains, Nature Chemistry, 14, 196, 10.1038/s41557-021-00840-w · DOI
  16. 10.1101/2024.03.14.584940 · DOI
  17. 10.1101/2024.02.03.578735v2 · DOI
  18. 2019, Structural characterization of N-WASP domain V using MD simulations with NMR and SAXS data, Biophysical Journal, 116, 1216, 10.1016/j.bpj.2019.02.015 · DOI
  19. 2024, HDX–MS finds that partial unfolding with sequential domain activation controls condensation of a cellular stress marker, Proceedings of the National Academy of Sciences, 121, e2321606121, 10.1073/pnas.2321606121 · DOI
  20. 10.1073/pnas.1912055117 · DOI
  21. 10.1016/j.str.2019.05.001 · DOI
  22. 2021, A data-driven hydrophobicity scale for predicting liquid–liquid phase separation of proteins, The Journal of Physical Chemistry B, 125, 4046, 10.1021/acs.jpcb.0c11479 · DOI
  23. 10.1073/pnas.1516277113 · DOI
  24. 10.1016/j.bpj.2013.12.046 · DOI
  25. 10.1021/ja044834j · DOI
  26. 2016, Investigating the role of large-scale domain dynamics in protein-protein interactions, Frontiers in Molecular Biosciences, 3, 54
  27. 2018, Sequence determinants of protein phase behavior from a coarse-grained model, PLoS computational biology, 14, e1005941, 10.1371/journal.pcbi.1005941 · DOI
  28. 2017, OpenMM 7: Rapid development of high performance algorithms for molecular dynamics, PLoS computational biology, 13, e1005659, 10.1371/journal.pcbi.1005659 · DOI · Paper page
  29. 2023, The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity, Nature structural & molecular biology, 30, 309, 10.1038/s41594-023-00920-0 · DOI
  30. 2020, The effects of chain length on the structural properties of intrinsically disordered proteins in concentrated solutions, The Journal of Physical Chemistry B, 124, 11843, 10.1021/acs.jpcb.0c09635 · DOI
  31. 2023, Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions, Nature communications, 14, 5527, 10.1038/s41467-023-41274-x · DOI
  32. 10.1074/jbc.RA119.009845 · DOI
  33. 2017, Phosphorylation induces sequence-specific conformational switches in the RNA polymerase II C-terminal domain, Nature communications, 8, 15233, 10.1038/ncomms15233 · DOI
  34. 10.1021/jacs.0c02088 · DOI
  35. 2021, Conformational landscape of multidomain SMAD proteins, Computational and Structural Biotechnology Journal, 19, 5210, 10.1016/j.csbj.2021.09.009 · DOI
  36. 2021, Extended disorder at the cell surface: The conformational landscape of the ectodomains of syndecans, Matrix Biology Plus, 12, 100081, 10.1016/j.mbplus.2021.100081 · DOI
  37. 2010, PRIMO/PRIMONA: a coarse-grained model for proteins and nucleic acids that preserves near-atomistic accuracy, Proteins: Structure, Function, and Bioinformatics, 78, 1266, 10.1002/prot.22645 · DOI
  38. 2023, Disordered Domain Shifts the Conformational Ensemble of the Folded Regulatory Domain of the Multidomain Oncoprotein c-Src, Biomacromolecules, 24, 714, 10.1021/acs.biomac.2c01158 · DOI
  39. 2018, Probing the architecture of a multi-PDZ domain protein: Structure of PDZK1 in solution, Structure, 26, 1522, 10.1016/j.str.2018.07.016 · DOI
  40. 2017, Structural disorder and induced folding within two cereal, ABA stress and ripening (ASR) proteins, Scientific reports, 7, 15544, 10.1038/s41598-017-15299-4 · DOI
  41. 10.1038/nrm2144 · DOI
  42. 2024, One bead per residue can describe all-atom protein structures, Structure, 32, 97, 10.1016/j.str.2023.10.013 · DOI
  43. 2022, Molecular interactions underlying the phase separation of HP1a: role of phosphorylation, ligand and nucleic acid binding, Nucleic Acids Research, 50, 12702, 10.1093/nar/gkac1194 · DOI
  44. Hesgrove CS , Nguyen KH , Biswas S , Childs CA , Shraddha K , Medina BX , Alvarado V , Yu F , Sukenik S , Malferrari M , et al. Tardigrade CAHS Proteins Act as Molecular Swiss Army Knives to Mediate Desiccation Tolerance Through Multiple Mechanisms. bioRxiv. 2021; p. 2021–08. · DOI
  45. 2020, Sequence-dependent correlated segments in the intrinsically disordered region of ChiZ, Biomolecules, 10, 946, 10.3390/biom10060946 · DOI
  46. 1994, Parser for protein folding units, Proteins: Structure, Function, and Bioinformatics, 19, 256, 10.1002/prot.340190309 · DOI
  47. 10.1016/j.str.2006.09.002 · DOI
  48. 2019, Temperature dependence of intrinsically disordered proteins in simulations: What are we missing?, Journal of chemical theory and computation, 15, 2672, 10.1021/acs.jctc.8b01281 · DOI
  49. 2021, How multisite phosphorylation impacts the conformations of intrinsically disordered proteins, PLoS computational biology, 17, e1008939, 10.1371/journal.pcbi.1008939 · DOI · Paper page
  50. 10.1016/j.bpj.2017.08.030 · DOI
  51. 2021, Physics-driven coarsegrained model for biomolecular phase separation with near-quantitative accuracy, Nature Computational Science, 1, 732, 10.1038/s43588-021-00155-3 · DOI
  52. 2023, Effective Molecular Dynamics from Neural Network-Based Structure Prediction Models, Journal of Chemical Theory and Computation, 19, 1965, 10.1021/acs.jctc.2c01027 · DOI · Paper page
  53. 10.1126/sciadv.abc3786 · DOI
  54. 2022, Phase-separating RNA-binding proteins form heterogeneous distributions of clusters in subsaturated solutions, Proceedings of the National Academy of Sciences, 119, e2202222119, 10.1073/pnas.2202222119 · DOI
  55. 10.1016/j.jmb.2007.11.063 · DOI
  56. 10.1002/pro.435 · DOI
  57. 1998, Assembly of protein structure from sparse experimental data: an eicient Monte Carlo model, Proteins: Structure, Function, and Bioinformatics, 32, 475, 10.1002/(SICI)1097-0134(19980901)32:4<475::AID-PROT6>3.0.CO;2-F · DOI
  58. 2021, Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions, Nature communications, 12, 1085, 10.1038/s41467-021-21181-9 · DOI
  59. 10.1039/c5cp04858c · DOI
  60. 2023, Merizo: a rapid and accurate protein domain segmentation method using invariant point attention, Nature Communications, 14, 8445, 10.1038/s41467-023-43934-4 · DOI · Paper page
  61. 10.1073/pnas.1201807109 · DOI
  62. 10.1074/jbc.M117.802793 · DOI
  63. 2021, The disease associated tau35 fragment has an increased propensity to aggregate compared to full-length tau, Frontiers in Molecular Biosciences, 8, 779240, 10.3389/fmolb.2021.779240 · DOI
  64. 10.1016/j.sbi.2012.03.013 · DOI
  65. 2022, Salt-induced transitions in the conformational ensembles of intrinsically disordered proteins, The Journal of Physical Chemistry B, 126, 5959, 10.1021/acs.jpcb.2c03476 · DOI
  66. 2021, A multi-step nucleation process determines the kinetics of prion-like domain phase separation, Nature communications, 12, 4513, 10.1038/s41467-021-24727-z · DOI
  67. 10.1021/jacs.6b10272 · DOI
  68. 10.1093/nar/gkab063 · DOI
  69. 2020, Structural insights of the enzymes from the chitin utilization locus of Flavobacterium johnsoniae, Scientific Reports, 10, 13775, 10.1038/s41598-020-70749-w · DOI
  70. 10.1016/j.str.2016.08.018 · DOI
  71. 10.1016/j.jmb.2018.05.012 · DOI · Paper page
  72. 10.1016/j.cell.2015.09.015 · DOI
  73. 10.15252/embj.201696394 · DOI
  74. 2008, The MARTINI coarse-grained force field: extension to proteins, Journal of chemical theory and computation, 4, 819, 10.1021/ct700324x · DOI
  75. Moses D , Guadalupe K , Yu F , Flores E , Perez AR , McAnelly R , Shamoon NM , Kaur G , Cuevas-Zepeda E , Merg AD , et al. Structural biases in disordered proteins are prevalent in the cell. Nature Structural & Molecular Biology. 2024; p. 1–10. · DOI
  76. Mugnai ML , Chakraborty D , Kumar A , Nguyen HT , Zeno W , Stachowiak JC , Straub JE , Thirumalai D. Sizes, conformational fluctuations, and SAXS profiles for Intrinsically Disordered Proteins. bioRxiv. 2023; p. 2023–04. · DOI
  77. 2019, Molecular interactions underlying liquidliquid phase separation of the FUS low-complexity domain, Nature structural & molecular biology, 26, 637, 10.1038/s41594-019-0250-x · DOI · Paper page
  78. 10.1021/bi800900d · DOI
  79. 2008, Temperature dependence of the dissociation constants of several amino acids, Journal of Chemical & Engineering Data, 53, 619, 10.1021/je700067a · DOI
  80. 10.1103/PhysRevLett.95.218102 · DOI
  81. 10.1529/biophysj.107.108241 · DOI
  82. 10.1016/j.molcel.2015.01.013 · DOI · Paper page
  83. 2017, The metastasis suppressor KISS1 is an intrinsically disordered protein slightly more extended than a random coil, PLoS One, 12, e0172507, 10.1371/journal.pone.0172507 · DOI
  84. Ostendorp A , Ostendorp S , Zhou Y , Chaudron Z , Wolffram L , Rombi K , von Pein L , Falke S , Jeffries CM , Svergun DI , et al. Intrinsically disordered plant protein PARCL colocalizes with RNA in phase-separated condensates whose formation can be regulated by mutating the PLD. Journal of Biological Chemistry. 2022; 298(12). · DOI
  85. 1996, Electrostatic multipole representation of a polypeptide chain: an algorithm for simulation of polypeptide properties, Journal of computational chemistry, 17, 1033, 10.1002/(SICI)1096-987X(199606)17:8<1033::AID-JCC12>3.0.CO;2-F · DOI
  86. 10.1529/biophysj.107.126995 · DOI
  87. 10.1016/j.bpj.2022.12.013 · DOI
  88. 10.1002/pro.4094 · DOI
  89. 10.1126/science.aan5774 · DOI
  90. 10.1016/j.molcel.2022.06.024 · DOI
  91. 10.1016/j.molcel.2017.12.022 · DOI
  92. 2021, Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning and reduces neurodegeneration, The EMBO Journal, 40, e105001, 10.15252/embj.2020105001 · DOI
  93. 2017, The Henipavirus V protein is a prevalently unfolded protein with a zinc-finger domain involved in binding to DDB1, Molecular BioSystems, 13, 2254, 10.1039/C7MB00488E · DOI
  94. 2019, Protein network structure enables switching between liquid and gel states, Journal of the American Chemical Society, 142, 874
  95. 10.1073/pnas.2000223117 · DOI
  96. 2020, Orchestration of signaling by structural disorder in class 1 cytokine receptors, Cell Communication and Signaling, 18, 1
  97. 10.1073/pnas.2122523119 · DOI
  98. 2021, Structural insights into the interaction of the intrinsically disordered co-activator TIF2 with retinoic acid receptor heterodimer (RXR/RAR), Journal of molecular biology, 433, 166899, 10.1016/j.jmb.2021.166899 · DOI
  99. 10.1038/nsb0397-215 · DOI
  100. 10.1073/pnas.1907251116 · DOI
  101. Sieradzan AK , Czaplewski C , Krupa P , Mozolewska MA , Karczynska AS , Lipska AG , Lubecka EA , Golas E , Wirecki T , Makowski M , et al. Modeling the structure, dynamics, and transformations of proteins with the UNRES force field. Protein folding: Methods and protocols. 2022; p. 399–416. · DOI
  102. 2017, Segmental, Domain-Selective Perdeuteration and Small-Angle Neutron Scattering for Structural Analysis of Multi-Domain Proteins, Angewandte Chemie, 129, 9450, 10.1002/ange.201702904 · DOI
  103. 2021, Martini 3: a general purpose force field for coarse-grained molecular dynamics, Nature methods, 18, 382, 10.1038/s41592-021-01098-3 · DOI · Paper page
  104. 10.1126/sciadv.abg7653 · DOI
  105. 2023, Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation, JACS Au, 3, 834, 10.1021/jacsau.2c00646 · DOI
  106. 2021, Folded domain charge properties influence the conformational behavior of disordered tails, Current Research in Structural Biology, 3, 216, 10.1016/j.crstbi.2021.08.002 · DOI
  107. 2023, Improved predictions of phase behaviour of intrinsically disordered proteins by tuning the interaction range, Open Research Europe, 2, 94
  108. 2021, DEER-PREdict: Software for eicient calculation of spinlabeling EPR and NMR data from conformational ensembles, PLOS Computational Biology, 17, e1008551, 10.1371/journal.pcbi.1008551 · DOI
  109. 10.1073/pnas.2111696118 · DOI
  110. 10.1038/s41586-023-07004-5 · DOI
  111. 2022, Conformational ensembles of intrinsically disordered proteins and flexible multidomain proteins, Biochemical Society Transactions, 50, 541, 10.1042/BST20210499 · DOI
  112. 2022, Improving Martini 3 for disordered and multidomain proteins, Journal of Chemical Theory and Computation, 18, 2033, 10.1021/acs.jctc.1c01042 · DOI
  113. Thomasen FE , Skaalum T , Kumar A , Srinivasan S , Vanni S , Lindorff-Larsen K. Recalibration of protein interactions in Martini 3. bioRxiv. 2023; p. 2023–05.
  114. 2023, Modeling concentration-dependent phase separation processes involving peptides and RNA via residue-based coarse-graining, Journal of Chemical Theory and Computation, 19, 669, 10.1021/acs.jctc.2c00856 · DOI
  115. 10.1021/cr400525m · DOI
  116. 10.1093/NAR/GKAB1061 · DOI · Paper page
  117. 10.1016/j.cell.2018.06.006 · DOI
  118. 2022, Analytical Formulation and Field-Theoretic Simulation of Sequence-Specific Phase Separation of Protein-Like Heteropolymers with Short-and Long-Spatial-Range Interactions, The Journal of Physical Chemistry B, 126, 9222, 10.1021/acs.jpcb.2c06181 · DOI
  119. 2020, Purification and structural characterization of aggregation-prone human TDP-43 involved in neurodegenerative diseases, Iscience, 23, 101159, 10.1016/j.isci.2020.101159 · DOI
  120. 2023, Improved protein model in SPICA force field, Journal of Chemical Theory and Computation, 19, 8967, 10.1021/acs.jctc.3c01016 · DOI
  121. Yu F , Sukenik S. Structural preferences shape the entropic force of disordered protein ensembles. The Journal of Physical Chemistry B. 2023;. · DOI · Paper page
  122. Zhang Y , Li S , Gong X , Chen J. Toward Accurate Simulation of Coupling between Protein Secondary Structure and Phase Separation. Journal of the American Chemical Society. 2023;. · DOI
  123. 10.1021/acs.jcim.2c00974 · DOI
  124. 2021, EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction, Nature communications, 12, 986, 10.1038/s41467-021-21258-5 · DOI
  125. 2020, Molecular details of protein condensates probed by microsecond long atomistic simulations, The Journal of Physical Chemistry B, 124, 11671, 10.1021/acs.jpcb.0c10489 · DOI

Metadata

Authors
Cao, F., von Bülow, S., Tesei, G., & Lindorff-Larsen, K.
Affiliations
University of Copenhagen (DK)
ORCID
Venue
Protein Science
Publisher
openRxiv
Published
2024-02-07
Volume
33
Issue
11
Pages
e5172-e5172
ISSN
0961-8368 (ISSN-L)
DOI
10.1101/2024.02.03.578735
PMC
PMC11481261
OpenAlex
W4403460892
Cited by
134
References
1
Citations by year
2026: 65 · 2025: 62 · 2024: 7
FWCI
18.24
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Protein Science (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
Funders
  • European Molecular Biology Organization
  • Novo Nordisk
  • China Scholarship Council
  • Novo Nordisk Fonden (NNF18OC0032608, NNF18OC0033950)
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
coarse-grained models, multidomain proteins, intrinsically disordered proteins, domain-domain interactions, protein phase separation, protein self-association, protein conformational ensembles, protein folding stability
MeSH terms
Protein Domains, Models, Molecular, Protein Conformation, Proteins, Protein Folding, Molecular Dynamics Simulation, Intrinsically Disordered Proteins

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