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Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein

Nature Chemistry volume 14, pages 224–231 (2022)Cite this article

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Abstract

Highly charged intrinsically disordered proteins are essential regulators of chromatin structure and transcriptional activity. Here we identify a surprising mechanism of molecular competition that relies on the pronounced dynamical disorder present in these polyelectrolytes and their complexes. The highly positively charged human linker histone H1.0 (H1) binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. However, we show that the disordered regions of H1 retain their large-amplitude dynamics when bound to the nucleosome, which enables the highly negatively charged and disordered histone chaperone prothymosin α to efficiently invade the H1–nucleosome complex and displace H1 via a competitive substitution mechanism, vastly accelerating H1 dissociation. By integrating experiments and simulations, we establish a molecular model that rationalizes the remarkable kinetics of this process structurally and dynamically. Given the abundance of polyelectrolyte sequences in the nuclear proteome, this mechanism is likely to be widespread in cellular regulation.

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Fig. 1: H1 binds nucleosomes tightly but reversibly.
Fig. 2: H1 binds nucleosomes with diffusion-limited association rates.
Fig. 3: ProTα facilitates H1 dissociation from the nucleosome.
Fig. 4: H1 remains disordered and dynamic on the nucleosome.
Fig. 5: Mechanism of H1 chaperoning on the nucleosome by ProTα.

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Data availability

Data supporting the findings of this study are available within the paper and its Supplementary Information. Source data are provided with this paper.

Code availability

A custom WSTP add-on for Mathematica (Wolfram Research) used for the analysis of single-molecule fluorescence data is available upon request and at https://schuler.bioc.uzh.ch/programs. A modified version of GROMACS was used for coarse-grained simulations, which is available at https://github.com/bestlab/gromacs-2019.4.git.

References

  1. Habchi, J., Tompa, P., Longhi, S. & Uversky, V. N. Introducing protein intrinsic disorder. Chem. Rev. 114, 6561–6588 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Watson, M. & Stott, K. Disordered domains in chromatin-binding proteins. Essays Biochem. 63, 147–156 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Wright, P. E. & Dyson, H. J. Intrinsically disordered proteins in cellular signalling and regulation. Nat. Rev. Mol. Cell Biol. 16, 18–29 (2014).

    Article  Google Scholar 

  4. Fuxreiter, M. et al. Malleable machines take shape in eukaryotic transcriptional regulation. Nat. Chem. Biol. 4, 728–737 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vuzman, D. & Levy, Y. Intrinsically disordered regions as affinity tuners in protein–DNA interactions. Mol. Biosyst. 8, 47–57 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Borgia, A. et al. Extreme disorder in an ultrahigh-affinity protein complex. Nature 555, 61–66 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Turner, A. L. et al. Highly disordered histone H1–DNA model complexes and their condensates. Proc. Natl Acad. Sci. USA 115, 11964–11969 (2018).

  8. Srivastava, S. & Tirrell, M. V. Polyelectrolyte complexation. Adv. Chem. Phys. 161, 499–544 (2016).

    CAS  Google Scholar 

  9. van der Gucht, J., Spruijt, E., Lemmers, M. & Cohen Stuart, M. A. Polyelectrolyte complexes: bulk phases and colloidal systems. J. Colloid Interface Sci. 361, 407–422 (2011).

    Article  PubMed  Google Scholar 

  10. Gibbs, E. B. & Kriwacki, R. W. Linker histones as liquid-like glue for chromatin. Proc. Natl Acad. Sci. USA 115, 11868–11870 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schuler, B. et al. Binding without folding – the biomolecular function of disordered polyelectrolyte complexes. Curr. Opin. Struct. Biol. 60, 66–76 (2019).

    Article  PubMed  Google Scholar 

  13. Korolev, N., Allahverdi, A., Lyubartsev, A. P. & Nordenskiold, L. The polyelectrolyte properties of chromatin. Soft Matter 8, 9322–9333 (2012).

    Article  CAS  Google Scholar 

  14. Hergeth, S. P. & Schneider, R. The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle. EMBO Rep. 16, 1439–1453 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cutter, A. R. & Hayes, J. J. A brief review of nucleosome structure. FEBS Lett. 589, 2914–2922 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Öztürk, M. A., De, M., Cojocaru, V. & Wade, R. C. Chromatosome structure and dynamics from molecular simulations. Annu. Rev. Phys. Chem. 71, 101–119 (2020).

    Article  PubMed  Google Scholar 

  17. Willcockson, M. A. et al. H1 histones control the epigenetic landscape by local chromatin compaction. Nature 589, 293–298 (2021).

    Article  CAS  PubMed  Google Scholar 

  18. Gibson, B. A. et al. Organization of chromatin by intrinsic and regulated phase separation. Cell 179, 470–484, e421 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Flanagan, T. W. & Brown, D. T. Molecular dynamics of histone H1. Biochim. Biophys. Acta 1859, 468–475 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. George, E. M. & Brown, D. T. Prothymosin α is a component of a linker histone chaperone. FEBS Lett. 584, 2833–2836 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gomez-Marquez, J. & Rodríguez, P. Prothymosin α is a chromatin-remodelling protein in mammalian cells. Biochem. J. 333, 1–3 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Karetsou, Z. et al. Prothymosin α modulates the interaction of histone H1 with chromatin. Nucleic Acids Res. 26, 3111–3118 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peng, B. & Muthukumar, M. Modeling competitive substitution in a polyelectrolyte complex. J. Chem. Phys. 143, 243133 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mao, A. H., Crick, S. L., Vitalis, A., Chicoine, C. L. & Pappu, R. V. Net charge per residue modulates conformational ensembles of intrinsically disordered proteins. Proc. Natl Acad. Sci. USA 107, 8183–8188 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Müller-Späth, S. et al. Charge interactions can dominate the dimensions of intrinsically disordered proteins. Proc. Natl Acad. Sci. USA 107, 14609–14614 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lowary, P. T. & Widom, J. New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. J. Mol. Biol. 276, 19–42 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Fang, H., Clark, D. J. & Hayes, J. J. DNA and nucleosomes direct distinct folding of a linker histone H1 C-terminal domain. Nucleic Acids Res. 40, 1475–1484 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. White, A. E., Hieb, A. R. & Luger, K. A quantitative investigation of linker histone interactions with nucleosomes and chromatin. Sci. Rep. 6, 19122 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bednar, J. et al. Structure and dynamics of a 197 bp nucleosome in complex with linker histone H1. Mol. Cell 66, 384–397.e8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sridhar, A. et al. Emergence of chromatin hierarchical loops from protein disorder and nucleosome asymmetry. Proc. Natl Acad. Sci. USA 117, 7216–7224 (2020).

  31. Syed, S. H. et al. Single-base resolution mapping of H1–nucleosome interactions and 3D organization of the nucleosome. Proc. Natl Acad. Sci. USA 107, 9620–9625 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Record, M. T. Jr, Anderson, C. F. & Lohman, T. M. Thermodynamic analysis of ion effects on the binding and conformational equilibria of proteins and nucleic acids: the roles of ion association or release, screening, and ion effects on water activity. Q. Rev. Biophys. 11, 103–178 (1978).

    Article  CAS  PubMed  Google Scholar 

  33. Anderson, C. F. & Record, M. T. Jr. Salt-nucleic acid interactions. Annu. Rev. Phys. Chem. 46, 657–700 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Brown, D. T., Izard, T. & Misteli, T. Mapping the interaction surface of linker histone H10 with the nucleosome of native chromatin in vivo. Nat. Struct. Mol. Biol. 13, 250–255 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gansen, A. et al. High precision FRET studies reveal reversible transitions in nucleosomes between microseconds and minutes. Nat. Commun. 9, 4628 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gansen, A. et al. Nucleosome disassembly intermediates characterized by single-molecule FRET. Proc. Natl Acad. Sci. USA 106, 15308–15313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gopich, I. V. & Szabo, A. Decoding the pattern of photon colors in single-molecule FRET. J. Phys. Chem. B 113, 10965–10973 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lever, M. A., Th’ng, J. P., Sun, X. & Hendzel, M. J. Rapid exchange of histone H1.1 on chromatin in living human cells. Nature 408, 873–876 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Misteli, T., Gunjan, A., Hock, R., Bustin, M. & Brown, D. T. Dynamic binding of histone H1 to chromatin in living cells. Nature 408, 877–881 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Bednar, J., Hamiche, A. & Dimitrov, S. H1–nucleosome interactions and their functional implications. Biochim. Biophys. Acta 1859, 436–443 (2015).

    Article  PubMed  Google Scholar 

  41. Bryan, L. C. et al. Single-molecule kinetic analysis of HP1-chromatin binding reveals a dynamic network of histone modification and DNA interactions. Nucleic Acids Res. 45, 10504–10517 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Papamarcaki, T. & Tsolas, O. Prothymosin α binds to histone H1 in vitro. FEBS Lett. 345, 71–75 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Sottini, A. et al. Polyelectrolyte interactions enable rapid association and dissociation in high-affinity disordered protein complexes. Nat. Commun. 11, 5736 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Haritos, A. A., Salvin, S. B., Blacher, R., Stein, S. & Horecker, B. L. Parathymosin alpha: a peptide from rat tissues with structural homology to prothymosin alpha. Proc. Natl Acad. Sci. USA 82, 1050–1053 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen, T. Y., Cheng, Y. S., Huang, P. S. & Chen, P. Facilitated unbinding via multivalency-enabled ternary complexes: new paradigm for protein–DNA interactions. Acc. Chem. Res. 51, 860–868 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gibb, B. et al. Concentration-dependent exchange of replication protein A on single-stranded DNA revealed by single-molecule imaging. PLoS ONE 9, e87922 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kamar, R. I. et al. Facilitated dissociation of transcription factors from single DNA binding sites. Proc. Natl Acad. Sci. USA 114, E3251–E3257 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lewis, J. S. et al. Single-molecule visualization of fast polymerase turnover in the bacterial replisome. eLife 6, e23932 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Potoyan, D. A., Zheng, W. H., Komives, E. A. & Wolynes, P. G. Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network. Proc. Natl Acad. Sci. USA 113, 110–115 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. Wu, H., Dalal, Y. & Papoian, G. A. Binding dynamics of disordered linker histone H1 with a nucleosomal particle. J. Mol. Biol. 433, 166881 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Fang, H., Wei, S., Lee, T. H. & Hayes, J. J. Chromatin structure-dependent conformations of the H1 CTD. Nucleic Acids Res. 44, 9131–9141 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Soranno, A. et al. Quantifying internal friction in unfolded and intrinsically disordered proteins with single-molecule spectroscopy. Proc. Natl Acad. Sci. USA 109, 17800–17806 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nettels, D., Gopich, I. V., Hoffmann, A. & Schuler, B. Ultrafast dynamics of protein collapse from single-molecule photon statistics. Proc. Natl. Acad. Sci. USA 104, 2655–2660 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kenzaki, H. & Takada, S. Partial unwrapping and histone tail dynamics in nucleosome revealed by coarse-grained molecular simulations. PLoS Comput. Biol. 11, e1004443 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zhang, B., Zheng, W., Papoian, G. A. & Wolynes, P. G. Exploring the free energy landscape of nucleosomes. J. Am. Chem. Soc. 138, 8126–8133 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Holmstrom, E. D., Liu, Z. W., Nettels, D., Best, R. B. & Schuler, B. Disordered RNA chaperones can enhance nucleic acid folding via local charge screening. Nat. Commun. 10, 245 (2019).

    Article  Google Scholar 

  57. Korolev, N., Fan, Y., Lyubartsev, A. P. & Nordenskiold, L. Modelling chromatin structure and dynamics: status and prospects. Curr. Opin. Struct. Biol. 22, 151–159 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Lu, X., Hamkalo, B., Parseghian, M. H. & Hansen, J. C. Chromatin condensing functions of the linker histone C-terminal domain are mediated by specific amino acid composition and intrinsic protein disorder. Biochemistry 48, 164–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Shoemaker, B. A., Portman, J. J. & Wolynes, P. G. Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc. Natl Acad. Sci. USA 97, 8868–8873 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vareli, K., Tsolas, O. & Frangou-Lazaridis, M. Regulation of prothymosin α during the cell cycle. Eur. J. Biochem. 238, 799–806 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Wang, S. et al. Linker histone defines structure and self-association behaviour of the 177 bp human chromatosome. Sci. Rep. 11, 380 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Catez, F., Ueda, T. & Bustin, M. Determinants of histone H1 mobility and chromatin binding in living cells. Nat. Struct. Mol. Biol. 13, 305–310 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Annalisa, I. & Robert, S. The role of linker histone H1 modifications in the regulation of gene expression and chromatin dynamics. Biochim. Biophys. Acta 1859, 486–495 (2015).

    Google Scholar 

  64. Privalov, P. L., Dragan, A. I. & Crane-Robinson, C. Interpreting protein/DNA interactions: distinguishing specific from non-specific and electrostatic from non-electrostatic components. Nucleic Acids Res. 39, 2483–2491 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Shakya, A., Park, S., Rana, N. & King, J. T. Liquid-liquid phase separation of histone proteins in cells: role in chromatin organization. Biophys. J. 118, 753–764 (2020).

    Article  CAS  PubMed  Google Scholar 

  66. Scott, K. A., Steward, A., Fowler, S. B. & Clarke, J. Titin; a multidomain protein that behaves as the sum of its parts. J. Mol. Biol. 315, 819–829 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Kilic, S., Bachmann, A. L., Bryan, L. C. & Fierz, B. Multivalency governs HP1α association dynamics with the silent chromatin state. Nat. Commun. 6, 7313 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Lowary, P. T. & Widom, J. New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. J. Mol. Biol. 276, 19–42 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Dyer, P. N. et al. Reconstitution of Nnucleosome core particles from recombinant histones and DNA. Methods Enzymol. 375, 23–44 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Müller, B. K., Zaychikov, E., Bräuchle, C. & Lamb, D. C. Pulsed interleaved excitation. Biophys. J. 89, 3508–3522 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Klehs, K. et al. Increasing the brightness of cyanine fluorophores for single-molecule and superresolution imaging. ChemPhysChem 15, 637–641 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Aitken, C. E., Marshall, R. A. & Puglisi, J. D. An oxygen scavenging system for improvement of dye stability in single-molecule fluorescence experiments. Biophys. J. 94, 1826–1835 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ha, T. & Tinnefeld, P. Photophysics of fluorescence probes for single-molecule biophysics and super-resolution imaging. Ann. Rev. Phys. Chem. 63, 595–617 (2012).

  74. Schuler, B. Application of single molecule Förster resonance energy transfer to protein folding. Methods Mol. Biol. 350, 115–138 (2007).

    CAS  PubMed  Google Scholar 

  75. Nettels, D., Gopich, I. V., Hoffmann, A. & Schuler, B. Ultrafast dynamics of protein collapse from single-molecule photon statistics. Proc. Natl Acad. Sci. USA 104, 2655–2660 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gopich, I. V., Nettels, D., Schuler, B. & Szabo, A. Protein dynamics from single-molecule fluorescence intensity correlation functions. J. Chem. Phys. 131, 095102 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Holmstrom, E. D. et al. Accurate transfer efficiencies, distance distributions, and ensembles of unfolded and intrinsically disordered proteins from single-molecule FRET. Methods Enzymol. 611, 287–325 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zheng, W. et al. Inferring properties of disordered chains from FRET transfer efficiencies. J. Chem. Phys. 148, 123329 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Gopich, I. V. & Szabo, A. Theory of the energy transfer efficiency and fluorescence lifetime distribution in single-molecule FRET. Proc. Natl Acad. Sci. USA 109, 7747–7752 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sisamakis, E., Valeri, A., Kalinin, S., Rothwell, P. J. & Seidel, C. A. M. Accurate single-molecule FRET studies using multiparameter fluorescence detection. Methods Enzymol. 475, 455–514 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Hellenkamp, B. et al. Precision and accuracy of single-molecule FRET measurements—a multi-laboratory benchmark study. Nat. Methods 15, 669–676 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zosel, F., Mercadante, D., Nettels, D. & Schuler, B. A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction. Nat. Commun. 9, 3332 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Chung, H. S. et al. Extracting rate coefficients from single-molecule photon trajectories and FRET efficiency histograms for a fast-folding protein. J. Phys. Chem. A 115, 3642–3656 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Viterbi, A. J. Error bounds for convolutional codes and an asymptotically optimum decoding algorithm. IEEE Trans. Inf. Theory 13, 260–269 (1967).

    Article  Google Scholar 

  85. Karanicolas, J. & Brooks, C. L. III The origins of asymmetry in the folding transition states of protein L and protein G. Protein Sci. 11, 2351–2361 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kim, Y. C. & Hummer, G. Coarse-grained models for simulations of multiprotein complexes: application to ubiquitin binding. J. Mol. Biol. 375, 1416–1433 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Yakovchuk, P., Protozanova, E. & Frank-Kamenetskii, M. D. Base-stacking and base-pairing contributions into thermal stability of the DNA double helix. Nucleic Acids Res. 34, 564–574 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhou, B. R. et al. Structural insights into the histone H1–nucleosome complex. Proc. Natl Acad. Sci. USA 110, 19390–19395 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhou, Y. B., Gerchman, S. E., Ramakrishnan, V., Travers, A. & Muyldermans, S. Position and orientation of the globular domain of linker histone H5 on the nucleosome. Nature 395, 402–405 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Berendsen, H. J. C., van der Spoel, D. & van Drunen, R. GROMACS: a message-passing parallel molecular dynamics implementation. Comp. Phys. Comm. 91, 43–56 (1995).

    Article  CAS  Google Scholar 

  91. van der Spoel, D. et al. GROMACS: fast, flexible, and free. J. Comput. Chem. 26, 1701–1718 (2005).

    Article  Google Scholar 

  92. Aznauryan, M. et al. Comprehensive structural and dynamical view of an unfolded protein from the combination of single-molecule FRET, NMR, and SAXS. Proc. Natl Acad. Sci. USA 113, E5389–E5398 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lin, L. I. A concordance correlation coefficient to evaluate reproducibility. Biometrics 45, 255–268 (1989).

    Article  CAS  PubMed  Google Scholar 

  94. Tribello, G. A., Bonomi, M., Branduardi, D., Camilloni, C. & Bussi, G. Plumed 2: new feathers for an old bird. Comput. Phys. Commun. 185, 604–613 (2014).

    Article  CAS  Google Scholar 

  95. Sugita, Y., Kitao, A. & Okamoto, Y. Multidimensional replica-exchange method for free-energy calculations. J. Chem. Phys. 113, 6042–6051 (2000).

    Article  CAS  Google Scholar 

  96. Kumar, S., Rosenberg, J. M., Bouzida, D., Swendsen, R. H. & Kollman, P. A. The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J. Comp. Chem. 13, 1011–1021 (1992).

    Article  CAS  Google Scholar 

  97. Shoup, D. & Szabo, A. Role of diffusion in ligand binding to macromolecules and cell-bound receptors. Biophys. J. 40, 33–39 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank I. König for providing ProTα, K. Buholzer and F. Sturzenegger for helpful discussion, F. Büchler and N. Wyss for excellent technical assistance and the Functional Genomics Center Zurich for performing mass spectrometry. This work utilized the computational resources of the National Institutes of Health HPC Biowulf cluster (http://hpc.nih.gov) and of Piz Daint at the CSCS Swiss National Supercomputing Centre. This project was funded by the Novo Nordisk Foundation (P.O.H.), the Carlsberg Foundation (P.O.H.), The Boehringer Ingelheim Fonds (S.K.), the Swiss National Science Foundation (B.S. and B.F.), École Polytechnique Fédérale de Lausanne (B.F.) and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (R.B.B.).

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Author notes

  1. Pétur O. Heidarsson

    Present address: Department of Biochemistry, Science Institute, University of Iceland, Reykjavík, Iceland

  2. Davide Mercadante

    Present address: School of Chemical Sciences, University of Auckland, Auckland, New Zealand

  3. Madeleine B. Borgia & Alessandro Borgia

    Present address: Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

  4. Sinan Kilic

    Present address: Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark

  5. These authors contributed equally: Pétur O. Heidarsson, Davide Mercadante.

Authors and Affiliations

  1. Department of Biochemistry, University of Zurich, Zurich, Switzerland

    Pétur O. Heidarsson, Davide Mercadante, Andrea Sottini, Daniel Nettels, Madeleine B. Borgia, Alessandro Borgia & Benjamin Schuler

  2. Institut des Sciences et Ingénierie Chimiques (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Sinan Kilic & Beat Fierz

  3. Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Robert B. Best

  4. Department of Physics, University of Zurich, Zurich, Switzerland

    Benjamin Schuler

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Contributions

P.O.H., D.M., R.B.B. and B.S. designed the research; P.O.H. and S.K. prepared the reconstituted nucleosomes; P.O.H., M.B.B., A.B., A.S., S.K. and B.F. prepared the fluorescently labelled and/or unlabelled proteins; P.O.H. and A.S. performed the single-molecule experiments; P.O.H., A.S., D.N. and B.S. analysed the single-molecule data; D.M. and R.B.B. performed and analysed the simulations; R.B.B., B.F. and B.S. supervised the research; and P.O.H. and B.S. wrote the paper with help from all authors.

Corresponding authors

Correspondence to Pétur O. Heidarsson, Robert B. Best or Benjamin Schuler.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–7, Tables 1–3 and references.

Reporting Summary

Supplementary Video 1

Ensemble of H1 bound to the nucleosome. H1 is represented in blue, DNA in grey and the core histones in white. The video shows 1,000 conformers of the H1–nucleosome complex, obtained from replica-exchange molecular dynamics simulations as described in the Methods.

Supplementary Video 2

Binding and dissociation trajectories of ProTα and H1 bound to the nucleosome. ProTα is shown in red, H1 in blue, DNA in grey and the core histones in white. The trajectory depicting the association of ProTα to the H1–nucleosome complex is concatenated with a trajectory showing the ProTα–H1 complex dissociating from the nucleosome (as indicated by the text displayed), where a ratchet bias with a force constant of 1 kJ mol−1 nm−2 is applied to the globular domain with respect to the dyad to enable dissociation during the accessible simulation time. The segments of the simulations shown correspond to ~5.0 × 105 time steps for ProTα binding and ~2 × 105 time steps for dissociation. Note that these times are more akin to transition path times for binding and dissociation than first passage times, which would be orders of magnitude longer.

Supplementary Data

Source data supporting information.

Source data

Source Data Fig. 1

Transfer efficiency histograms, binding isotherms and binding affinities.

Source Data Fig. 2

Fluorescence time trajectory, dwell times and association/dissociation rates.

Source Data Fig. 3

Fluorescence time trajectories, association/dissociation rates, transfer efficiency histograms and binding isotherms.

Source Data Fig. 4

The nsFCS data, transfer efficiency histograms and transfer efficiencies from experiment and simulation.

Source Data Fig. 5

Simulation data.

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Heidarsson, P.O., Mercadante, D., Sottini, A. et al. Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein. Nat. Chem. 14, 224–231 (2022). https://doi.org/10.1038/s41557-021-00839-3

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