Skip to main content
SpringerLink
Log in

Molecular Simulations of Intrinsically Disordered Proteins and Their Binding Mechanisms

  • Protocol
  • First Online:
Protein Folding

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2376))

Abstract

Intrinsically disordered proteins (IDPs) lack well-defined secondary or tertiary structures in solution but are found to be involved in a wide range of critical cellular processes that highlight their functional importance. IDPs usually undergo folding upon binding to their targets. Such binding coupled to folding behavior has widened our perspective on the protein structure–dynamics–function paradigm in molecular biology. However, characterizing the folding upon binding mechanism of IDPs experimentally remains quite challenging. Molecular simulations emerge as a potentially powerful tool that offers information complementary to experiments. Here we present a general computational framework for the molecular simulations of IDP folding upon binding processes that combines all-atom molecular dynamics (MD) and coarse-grained simulations. The classical all-atom molecular dynamics approach using GPU acceleration allows the researcher to explore the properties of the IDP conformational ensemble, whereas coarse-grained structure-based models implemented with parameters carefully calibrated to available experimental measurements can be used to simulate the entire folding upon binding process. We also discuss a set of tools for the analysis of MD trajectories and describe the details of the computational protocol to follow so that it can be adapted by the user to study any IDP in isolation and in complex with partners.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293(2):321–331

    Article  CAS  PubMed  Google Scholar 

  2. Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001) Intrinsically disordered protein. J Mol Graph Model 19(1):26–59

    Article  CAS  PubMed  Google Scholar 

  3. Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27(10):527–533

    Article  CAS  PubMed  Google Scholar 

  4. Papoian GA (2008) Proteins with weakly funneled energy landscapes challenge the classical structure–function paradigm. Proc Natl Acad Sci U S A 105(38):14237–14238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Obradovic Z, Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK (2003) Predicting intrinsic disorder from amino acid sequence. Proteins 53(S6):566–572

    Article  CAS  PubMed  Google Scholar 

  6. Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337(3):635–645

    Article  CAS  PubMed  Google Scholar 

  7. Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradovic Z (2002) Intrinsic disorder and protein function. Biochemistry 41(21):6573–6582

    Article  CAS  PubMed  Google Scholar 

  8. Shammas SL (2017) Mechanistic roles of protein disorder within transcription. Curr Opin Struct Biol 42:155–161

    Article  CAS  PubMed  Google Scholar 

  9. Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6(3):197–208

    Article  CAS  PubMed  Google Scholar 

  10. DeForte S, Uversky VN (2016) Intrinsically disordered proteins in PubMed: what can the tip of the iceberg tell us about what lies below? RSC Adv 6(14):11513–11521

    Article  CAS  Google Scholar 

  11. Tokuriki N, Tawfik DS (2009) Protein dynamism and evolvability. Science 324(5924):203–207

    Article  CAS  PubMed  Google Scholar 

  12. Zhou H-X (2012) Intrinsic disorder: signaling via highly specific but short-lived association. Trends Biochem Sci 37(2):43–48

    Article  CAS  PubMed  Google Scholar 

  13. Teilum K, Olsen JG, Kragelund BB (2009) Functional aspects of protein flexibility. Cell Mol Life Sci 66(14):2231

    Article  CAS  PubMed  Google Scholar 

  14. Dunker AK, Garner E, Guilliot S, Romero P, Albrecht K, Hart J, Obradovic Z, Kissinger C, Villafranca JE (1998) Protein disorder and the evolution of molecular recognition: theory, predictions and observations. Pac Symp Biocomput:473–484

    Google Scholar 

  15. Chu X, Wang J (2014) Specificity and affinity quantification of flexible recognition from underlying energy landscape topography. PLoS Comput Biol 10(8):e1003782

    Article  PubMed  PubMed Central  Google Scholar 

  16. Shoemaker BA, Portman JJ, Wolynes PG (2000) Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc Natl Acad Sci U S A 97(16):8868–8873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huang Y, Liu Z (2009) Kinetic advantage of intrinsically disordered proteins in coupled folding–binding process: a critical assessment of the “fly-casting” mechanism. J Mol Biol 393(5):1143–1159

    Article  CAS  PubMed  Google Scholar 

  18. Uversky VN, Oldfield CJ, Dunker AK (2005) Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 18(5):343–384

    Article  CAS  PubMed  Google Scholar 

  19. Pontius BW (1993) Close encounters: why unstructured, polymeric domains can increase rates of specific macromolecular association. Trends Biochem Sci 18(5):181–186

    Article  CAS  PubMed  Google Scholar 

  20. Umezawa K, Ohnuki J, Higo J, Takano M (2016) Intrinsic disorder accelerates dissociation rather than association. Proteins 84(8):1124–1133

    Article  CAS  PubMed  Google Scholar 

  21. Xie H, Vucetic S, Iakoucheva LM, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN (2007) Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins. J Proteome Res 6(5):1917–1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Csizmok V, Follis AV, Kriwacki RW, Forman-Kay JD (2016) Dynamic protein interaction networks and new structural paradigms in signaling. Chem Rev 116(11):6424–6462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12(1):54–60

    Article  CAS  PubMed  Google Scholar 

  24. Wright PE, Dyson HJ (2009) Linking folding and binding. Curr Opin Struct Biol 19(1):31–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Koshland DE (1958) Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci U S A 44(2):98–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tsai C-J, Ma B, Nussinov R (1999) Folding and binding cascades: shifts in energy landscapes. Proc Natl Acad Sci U S A 96(18):9970–9972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bosshard HR (2001) Molecular recognition by induced fit: how fit is the concept? Physiology 16(4):171–173

    Article  CAS  Google Scholar 

  28. Csermely P, Palotai R, Nussinov R (2010) Induced fit, conformational selection and independent dynamic segments: an extended view of binding events. Trends Biochem Sci 35(10):539–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kiefhaber T, Bachmann A, Jensen KS (2012) Dynamics and mechanisms of coupled protein folding and binding reactions. Curr Opin Struct Biol 22(1):21–29

    Article  CAS  PubMed  Google Scholar 

  30. Okazaki K-I, Takada S (2008) Dynamic energy landscape view of coupled binding and protein conformational change: induced-fit versus population-shift mechanisms. Proc Natl Acad Sci U S A 105(32):11182–11187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhou H-X (2010) From induced fit to conformational selection: a continuum of binding mechanism controlled by the timescale of conformational transitions. Biophys J 98(6):L15–L17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hammes GG, Chang Y-C, Oas TG (2009) Conformational selection or induced fit: a flux description of reaction mechanism. Proc Natl Acad Sci U S A 106(33):13737–13741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dyson HJ, Wright PE (1998) Equilibrium NMR studies of unfolded and partially folded proteins. Nat Struct Biol 5:499–503

    Article  CAS  PubMed  Google Scholar 

  34. Mukhopadhyay S, Krishnan R, Lemke EA, Lindquist S, Deniz AA (2007) A natively unfolded yeast prion monomer adopts an ensemble of collapsed and rapidly fluctuating structures. Proc Natl Acad Sci U S A 104(8):2649–2654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eliezer D (2009) Biophysical characterization of intrinsically disordered proteins. Curr Opin Struct Biol 19(1):23–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhu F, Kapitan J, Tranter GE, Pudney PD, Isaacs NW, Hecht L, Barron LD (2008) Residual structure in disordered peptides and unfolded proteins from multivariate analysis and ab initio simulation of Raman optical activity data. Proteins 70(3):823–833

    Article  CAS  PubMed  Google Scholar 

  37. Fuxreiter M, Simon I, Friedrich P, Tompa P (2004) Preformed structural elements feature in partner recognition by intrinsically unstructured proteins. J Mol Biol 338(5):1015–1026

    Article  CAS  PubMed  Google Scholar 

  38. Knott M, Best RB (2012) A preformed binding interface in the unbound ensemble of an intrinsically disordered protein: evidence from molecular simulations. PLoS Comput Biol 8(7):e1002605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Arai M, Sugase K, Dyson HJ, Wright PE (2015) Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding. Proc Natl Acad Sci U S A 112(31):9614–9619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chu X, Wang Y, Gan L, Bai Y, Han W, Wang E, Wang J (2012) Importance of electrostatic interactions in the association of intrinsically disordered histone chaperone Chz1 and histone H2A. Z-H2B. PLoS Comput Biol 8(7):e1002608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Iešmantavičius V, Dogan J, Jemth P, Teilum K, Kjaergaard M (2014) Helical propensity in an intrinsically disordered protein accelerates ligand binding. Angew Chem Int Ed 53(6):1548–1551

    Article  Google Scholar 

  42. Rauscher S, Gapsys V, Gajda MJ, Zweckstetter M, de Groot BL, Grubmüller H (2015) Structural ensembles of intrinsically disordered proteins depend strongly on force field: a comparison to experiment. J Chem Theory Comput 11(11):5513–5524

    Article  CAS  PubMed  Google Scholar 

  43. Best RB, Zheng W, Mittal J (2014) Balanced protein–water interactions improve properties of disordered proteins and non-specific protein association. J Chem Theory Comput 10(11):5113–5124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot BL, Grubmüller H, MacKerell A (2017) CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods 14(1):71–73

    Article  CAS  PubMed  Google Scholar 

  45. Best RB, Zhu X, Shim J, Lopes PE, Mittal J, Feig M, MacKerell AD Jr (2012) Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone ϕ, ψ and side-chain χ1 and χ2 dihedral angles. J Chem Theory Comput 8(9):3257–3273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Piana S, Lindorff-Larsen K, Shaw DE (2011) How robust are protein folding simulations with respect to force field parameterization? Biophys J 100(9):L47–L49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Piana S, Donchev AG, Robustelli P, Shaw DE (2015) Water dispersion interactions strongly influence simulated structural properties of disordered protein states. J Phys Chem B 119(16):5113–5123

    Article  CAS  PubMed  Google Scholar 

  48. Shaw DE, Deneroff MM, Dror RO, Kuskin JS, Larson RH, Salmon JK, Young C, Batson B, Bowers KJ, Chao JC (2008) Anton, a special-purpose machine for molecular dynamics simulation. Commun ACM 51(7):91–97

    Article  Google Scholar 

  49. Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) How fast-folding proteins fold. Science 334(6055):517–520

    Article  CAS  PubMed  Google Scholar 

  50. Lindorff-Larsen K, Trbovic N, Maragakis P, Piana S, Shaw DE (2012) Structure and dynamics of an unfolded protein examined by molecular dynamics simulation. J Am Chem Soc 134(8):3787–3791

    Article  CAS  PubMed  Google Scholar 

  51. Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314(1):141–151

    Article  CAS  Google Scholar 

  52. Torrie GM, Valleau JP (1977) Nonphysical sampling distributions in Monte Carlo free-energy estimation: umbrella sampling. J Comput Phys 23(2):187–199

    Article  Google Scholar 

  53. Laio A, Parrinello M (2002) Escaping free-energy minima. Proc Natl Acad Sci U S A 99(20):12562–12566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Stanley N, Esteban-Martín S, De Fabritiis G (2014) Kinetic modulation of a disordered protein domain by phosphorylation. Nat Commun 5:ncomms6272

    Article  Google Scholar 

  55. Bryngelson JD, Onuchic JN, Socci ND, Wolynes PG (1995) Funnels, pathways, and the energy landscape of protein folding: a synthesis. Proteins 21(3):167–195

    Article  CAS  PubMed  Google Scholar 

  56. Clementi C, Nymeyer H, Onuchic JN (2000) Topological and energetic factors: what determines the structural details of the transition state ensemble and “en-route” intermediates for protein folding? An investigation for small globular proteins. J Mol Biol 298(5):937–953

    Article  CAS  PubMed  Google Scholar 

  57. Levy Y, Cho SS, Onuchic JN, Wolynes PG (2005) A survey of flexible protein binding mechanisms and their transition states using native topology based energy landscapes. J Mol Biol 346(4):1121–1145

    Article  CAS  PubMed  Google Scholar 

  58. Levy Y, Onuchic JN, Wolynes PG (2007) Fly-casting in protein-DNA binding: frustration between protein folding and electrostatics facilitates target recognition. J Am Chem Soc 129(4):738–739

    Article  CAS  PubMed  Google Scholar 

  59. Levy Y, Wolynes PG, Onuchic JN (2004) Protein topology determines binding mechanism. Proc Natl Acad Sci U S A 101(2):511–516

    Article  CAS  PubMed  Google Scholar 

  60. Chu X, Gan L, Wang E, Wang J (2013) Quantifying the topography of the intrinsic energy landscape of flexible biomolecular recognition. Proc Natl Acad Sci U S A 110(26):E2342–E2351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. De Sancho D, Best RB (2012) Modulation of an IDP binding mechanism and rates by helix propensity and non-native interactions: association of HIF1α with CBP. Mol BioSyst 8(1):256–267

    Article  PubMed  Google Scholar 

  62. Ganguly D, Chen J (2011) Topology-based modeling of intrinsically disordered proteins: balancing intrinsic folding and intermolecular interactions. Proteins 79(4):1251–1266

    Article  CAS  PubMed  Google Scholar 

  63. Turjanski AG, Gutkind JS, Best RB, Hummer G (2008) Binding-induced folding of a natively unstructured transcription factor. PLoS Comput Biol 4(4):e1000060

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wang J, Wang Y, Chu X, Hagen SJ, Han W, Wang E (2011) Multi-scaled explorations of binding-induced folding of intrinsically disordered protein inhibitor IA3 to its target enzyme. PLoS Comput Biol 7(4):e1001118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26(16):1701–1718

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  67. Schrodinger, LLC (2015) The PyMOL Molecular Graphics System, Version 1.8

    Google Scholar 

  68. Noel JK, Whitford PC, Sanbonmatsu KY, Onuchic JN (2010) SMOG@ ctbp: simplified deployment of structure-based models in GROMACS. Nucleic Acids Res 38(suppl 2):W657–W661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Radhakrishnan I, Pérez-Alvarado GC, Dyson HJ, Wright PE (1998) Conformational preferences in the Ser133-phosphorylated and non-phosphorylated forms of the kinase inducible transactivation domain of CREB. FEBS Lett 430(3):317–322

    Article  CAS  PubMed  Google Scholar 

  70. Radhakrishnan I, Pérez-Alvarado GC, Parker D, Dyson HJ, Montminy MR, Wright PE (1997) Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator: coactivator interactions. Cell 91(6):741–752

    Article  CAS  PubMed  Google Scholar 

  71. Zor T, De Guzman RN, Dyson HJ, Wright PE (2004) Solution structure of the KIX domain of CBP bound to the transactivation domain of c-Myb. J Mol Biol 337(3):521–534

    Article  CAS  PubMed  Google Scholar 

  72. Zor T, Mayr BM, Dyson HJ, Montminy MR, Wright PE (2002) Roles of phosphorylation and helix propensity in the binding of the KIX domain of CREB-binding protein by constitutive (c-Myb) and inducible (CREB) activators. J Biol Chem 277(44):42241–42248

    Article  CAS  PubMed  Google Scholar 

  73. Hess B, Bekker H, Berendsen HJ, Fraaije JG (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18(12):1463–1472

    Article  CAS  Google Scholar 

  74. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126(1):014101

    Article  PubMed  Google Scholar 

  75. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103(19):8577–8593

    Article  CAS  Google Scholar 

  76. Parrinello M, Rahman A (1981) Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52(12):7182–7190

    Article  CAS  Google Scholar 

  77. Sobolev V, Sorokine A, Prilusky J, Abola EE, Edelman M (1999) Automated analysis of interatomic contacts in proteins. Bioinformatics 15(4):327–332

    Article  CAS  PubMed  Google Scholar 

  78. Azia A, Levy Y (2009) Nonnative electrostatic interactions can modulate protein folding: molecular dynamics with a grain of salt. J Mol Biol 393(2):527–542

    Article  CAS  PubMed  Google Scholar 

  79. Givaty O, Levy Y (2009) Protein sliding along DNA: dynamics and structural characterization. J Mol Biol 385(4):1087–1097

    Article  CAS  PubMed  Google Scholar 

  80. Morrone A, Giri R, Brunori M, Gianni S (2012) Reassessing the folding of the KIX domain: evidence for a two-state mechanism. Protein Sci 21(11):1775–1779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Horng J-C, Tracz SM, Lumb KJ, Raleigh DP (2005) Slow folding of a three-helix protein via a compact intermediate. Biochemistry 44(2):627–634

    Article  CAS  PubMed  Google Scholar 

  82. Tollinger M, Kloiber K, Ágoston B, Dorigoni C, Lichtenecker R, Schmid W, Konrat R (2006) An isolated helix persists in a sparsely populated form of KIX under native conditions. Biochemistry 45(29):8885–8893

    Article  CAS  PubMed  Google Scholar 

  83. Wei Y, Horng J-C, Vendel AC, Raleigh DP, Lumb KJ (2003) Contribution to stability and folding of a buried polar residue at the CARM1 methylation site of the KIX domain of CBP. Biochemistry 42(23):7044–7049

    Article  CAS  PubMed  Google Scholar 

  84. Lifson S, Roig A (1961) On the theory of helix—coil transition in polypeptides. J Chem Res 34(6):1963–1974

    CAS  Google Scholar 

  85. Socci N, Onuchic JN, Wolynes PG (1996) Diffusive dynamics of the reaction coordinate for protein folding funnels. J Chem Res 104(15):5860–5868

    CAS  Google Scholar 

  86. Cho SS, Levy Y, Wolynes PG (2006) P versus Q: structural reaction coordinates capture protein folding on smooth landscapes. Proc Natl Acad Sci U S A 103(3):586–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Oliveira RJ, Whitford PC, Chahine J, Wang J, Onuchic JN, Leite VB (2010) The origin of nonmonotonic complex behavior and the effects of nonnative interactions on the diffusive properties of protein folding. Biophys J 99(2):600–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Šali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234(3):779–815

    Article  PubMed  Google Scholar 

  89. Chwastyk M, Bernaola AP, Cieplak M (2015) Statistical radii associated with amino acids to determine the contact map: fixing the structure of a type I cohesin domain in the clostridium thermocellum cellulosome. Phys Biol 12(4):046002

    Article  PubMed  Google Scholar 

  90. Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22(12):2577–2637

    Article  CAS  PubMed  Google Scholar 

  91. Veitshans T, Klimov D, Thirumalai D (1997) Protein folding kinetics: timescales, pathways and energy landscapes in terms of sequence-dependent properties. Fold Des 2(1):1–22

    Article  CAS  PubMed  Google Scholar 

  92. Kouza M, Li MS, O'Brien EP, Hu C-K, Thirumalai D (2006) Effect of finite size on cooperativity and rates of protein folding. J Phys Chem A 110(2):671–676

    Article  CAS  PubMed  Google Scholar 

  93. Kumar S, Rosenberg JM, Bouzida D, Swendsen RH, Kollman PA (1992) The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J Comput Chem 13(8):1011–1021

    Article  CAS  Google Scholar 

  94. Barducci A, Bussi G, Parrinello M (2008) Well-tempered metadynamics: a smoothly converging and tunable free-energy method. Phys Rev Lett 100(2):020603

    Article  PubMed  Google Scholar 

  95. Sharma R, De Sancho D, Muñoz V (2017) Interplay between the folding mechanism and binding modes in folding coupled to binding processes. Phys Chem Chem Phys 19(42):28512–28516

    Article  CAS  PubMed  Google Scholar 

  96. Huang Y, Liu Z (2010) Smoothing molecular interactions: the “kinetic buffer” effect of intrinsically disordered proteins. Proteins 78(16):3251–3259

    Article  CAS  PubMed  Google Scholar 

  97. Law SM, Gagnon JK, Mapp AK, Brooks CL (2014) Prepaying the entropic cost for allosteric regulation in KIX. Proc Natl Acad Sci U S A 111(33):12067–12072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was funded by Advanced Grant ERC-2012-ADG-323059 from the European Research Council to V. M. V. M. also acknowledges support from the Keck foundation, the CREST Center for Cellular and Biomolecular Machines (NSF-CREST-1547848) and the NSF (NSF-MCB-1616759).

Author information

Authors and Affiliations

  1. IMDEA Nanosciences, Madrid, Spain

    Xiakun Chu

  2. Department of Bioengineering, School of Engineering, University of California, Merced, CA, USA

    Suhani Nagpal

  3. Department of Bioengineering and Center for Cellular and Biomolecular Machines, University of California Merced, Merced, CA, USA

    Victor Muñoz

Authors
  1. Xiakun Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suhani Nagpal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Victor Muñoz .

Editor information

Editors and Affiliations

  1. Department of Bioengineering and Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, USA

    Victor Muñoz

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Chu, X., Nagpal, S., Muñoz, V. (2022). Molecular Simulations of Intrinsically Disordered Proteins and Their Binding Mechanisms. In: Muñoz, V. (eds) Protein Folding. Methods in Molecular Biology, vol 2376. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1716-8_19

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1716-8_19

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1715-1

  • Online ISBN: 978-1-0716-1716-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation