Science Bulletin

, Volume 60, Issue 1, pp 76–85 | Cite as

The principle of compromise in competition: exploring stability condition of protein folding

  • Ji Xu
  • Mengzhi Han
  • Ying RenEmail author
  • Jinghai Li
Article Chemistry


Thermodynamic hypothesis and kinetic stability are currently used to understand protein folding. The former assumes that free energy minimum is the exclusive dominant mechanism in most cases, while the latter shows that some proteins have even lower free energy in intermediate states and their native states are kinetically trapped in the higher free energy region. This article explores the stability condition of protein structures on the basis of our study of complex chemical systems. We believe that separating one from another is not reasonable since they should be coupled, and protein structures should be dominated by at least two mechanisms resulting in different characteristic states. It is concluded that: (1) Structures of proteins are dynamic, showing multiple characteristic states emerging alternately and each dominated by a respective mechanism. (2) Compromise in competition of multiple dominant mechanisms might be the key to understanding the stability of protein structures. (3) The dynamic process of protein folding should be depicted through the time series of both its energetic and structural changes, which is much meaningful and applicable than the free energy landscape.


Protein folding Dynamic structure Multiple mechanisms Compromise in competition Mesoscale Stability 



This work was supported by the National Natural Science Foundation of China (21103195) and the Knowledge Innovation Program of Chinese Academy of Sciences (KGCX2-YW-124). We especially thank Profs. Chih-chen Wang and Ruiming Xu (Institute of Biophysics, Chinese Academy of Sciences, China) for their fruitful discussions and helpful comments.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

Supplementary Video 1

The trajectory transformations from the starting structure to C3. Color scheme is the same as Fig. 2(b). (MP4 8312 kb)

Supplementary Video 2

The trajectory transformations from C3 to C2. Color scheme is the same as Fig. 2(b). (MP4 5773 kb)

Supplementary Video 3

The trajectory transformations from C2 to C1. Color scheme is the same as Fig. 2(b). (MP4 10956 kb)


  1. 1.
    Shevchenko A, Wilm M, Vorm O et al (1996) Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal Chem 68:850–858CrossRefGoogle Scholar
  2. 2.
    Guo M, Xu Y, Gruebele M (2012) Temperature dependence of protein folding kinetics in living cells. Proc Natl Acad Sci USA 190:17863–17867CrossRefGoogle Scholar
  3. 3.
    Vila-Vicosa D, Campos SRR, Baptista AM et al (2012) Reversibility of prion misfolding: Insights from constant-pH molecular dynamics simulations. J Phys Chem B 116:8812–8821CrossRefGoogle Scholar
  4. 4.
    Ren Y, Gao J, Xu J et al (2012) Key factors in chaperonin-assisted protein folding. Particuology 10:105–116Google Scholar
  5. 5.
    Dill KA, MacCallum JL (2012) The protein-folding problem, 50 years on. Science 338:1042–1046CrossRefGoogle Scholar
  6. 6.
    Chruszcz M, Potrzebowski W, Zimmerman MD et al (2008) Analysis of solvent content and oligomeric states in protein crystals–does symmetry matter? Protein Sci 17:623–632CrossRefGoogle Scholar
  7. 7.
    Frauenfelder H, Sligar SG, Wolynes PG (1991) The energy landscapes and motions of proteins. Science 254:1598–1603CrossRefGoogle Scholar
  8. 8.
    Selvin PR (2000) The renaissance of fluorescence resonance energy transfer. Nat Struct Biol 7:730–734CrossRefGoogle Scholar
  9. 9.
    Clausen-Schaumann H, Seitz M, Krautbauer R et al (2000) Force spectroscopy with single bio-molecules. Curr Opin Chem Biol 4:524–530CrossRefGoogle Scholar
  10. 10.
    Callender RH, Dyer RB, Gilmanshin R et al (1998) Fast events in protein folding: the time evolution of primary processes. Annu Rev Phys Chem 49:173–202CrossRefGoogle Scholar
  11. 11.
    Krishna MMG, Hoang L, Lin Y et al (2004) Hydrogen exchange methods to study protein folding. Methods 34:51–64CrossRefGoogle Scholar
  12. 12.
    Xu J, Ren Y, Li J (2013) Multiscale simulations of protein folding: application to formation of secondary structures. J Biomol Struct Dyn 31:779–787CrossRefGoogle Scholar
  13. 13.
    Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223–230CrossRefGoogle Scholar
  14. 14.
    Scheraga HA, Khalili M, Liwo A (2007) Protein-folding dynamics: overview of molecular simulation techniques. Annu Rev Phys Chem 58:57–83CrossRefGoogle Scholar
  15. 15.
    Dill KA, Ozkan SB, Shell MS et al (2008) The protein folding problem. Annu Rev Biophys 37:289–316CrossRefGoogle Scholar
  16. 16.
    Dill KA (1985) Theory for the folding and stability of globular proteins. Biochemistry 24:1501–1509CrossRefGoogle Scholar
  17. 17.
    Lindorff-Larsen K, Piana S, Dror RO et al (2011) How fast-folding proteins fold. Science 334:517–520CrossRefGoogle Scholar
  18. 18.
    Sanchez-Ruiz JM (2010) Protein kinetic stability. Biophys Chem 148:1–15CrossRefGoogle Scholar
  19. 19.
    Voelz VA, Bowman GR, Beauchamp K et al (2010) Molecular simulation of ab initio protein folding for a millisecond folder NTL9(1-39). J Am Chem Soc 132:1526–1528CrossRefGoogle Scholar
  20. 20.
    Fisher KE, Ruan B, Alexander PA et al (2006) Mechanism of the kinetically-controlled folding reaction of subtilisin. Biochemistry 46:640–651CrossRefGoogle Scholar
  21. 21.
    Sohl JL, Jaswal SS, Agard DA (1998) Unfolded conformations of α-lytic protease are more stable than its native state. Nature 395:817–819CrossRefGoogle Scholar
  22. 22.
    Wang Z, Mottonen J, Goldsmith EJ (1996) Kinetically controlled folding of the serpin plasminogen activator inhibitor 1. Biochemistry 35:16443–16448CrossRefGoogle Scholar
  23. 23.
    White JM (1994) Receptor mediated virus entry into cells. Cold Spring Harbor, Cold Spring Harbor Laboratory Press, New YorkGoogle Scholar
  24. 24.
    Chen Z, Lou J, Zhu C et al (2008) Flow-induced structural transition in the β-switch region of glycoprotein ib. Biophys J 95:1303–1313CrossRefGoogle Scholar
  25. 25.
    Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293:321–331CrossRefGoogle Scholar
  26. 26.
    Sugase K, Dyson HJ, Wright PE (2007) Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 447:1021–1025CrossRefGoogle Scholar
  27. 27.
    Li J, Ge W, Wang W et al (2013) From multiscale modeling to meso-science: a chemical engineering perspective principles, modeling, simulation, and application. Springer, BerlinCrossRefGoogle Scholar
  28. 28.
    Li J, Huang W (2014) Towards mesoscience the principle of compromise in competition. Springer, BerlinCrossRefGoogle Scholar
  29. 29.
    Prigogine I, Nicolis G (1971) Biological order, structure and instabilities. Q Rev Biophys 4:107–148CrossRefGoogle Scholar
  30. 30.
    Li J, Wen L, Ge W et al (1998) Dissipative structure in concurrent-up gas-solid flow. Chem Eng Sci 53:3367–3379CrossRefGoogle Scholar
  31. 31.
    Li J, Kwauk M (2003) Exploring complex systems in chemical engineering–the multi-scale methodology. Chem Eng Sci 58:521–535CrossRefGoogle Scholar
  32. 32.
    Li J, Kwauk M (1994) Particle-fluid two-phase flow: the energy-minimization multiscale method. Metallurgical Industry Press, BeijingGoogle Scholar
  33. 33.
    Teoh CL, Bekard IB, Asimakis P et al (2011) Shear flow induced changes in apolipoprotein c-ii conformation and amyloid fibril formation. Biochemistry 50:4046–4057CrossRefGoogle Scholar
  34. 34.
    Hart T, Hosszu LLP, Trevitt CR et al (2009) Folding kinetics of the human prion protein probed by temperature jump. Proc Natl Acad Sci USA 106:5651–5656CrossRefGoogle Scholar
  35. 35.
    Munoz V (2009) Downhill protein folding under pressure. Nat Methods 6:490–491CrossRefGoogle Scholar
  36. 36.
    Filipe LCS, Machuqueiro M, Baptista AM (2011) Unfolding the conformational behavior of peptide dendrimers: insights from molecular dynamics simulations. J Am Chem Soc 133:5042–5052CrossRefGoogle Scholar
  37. 37.
    Wolynes PG, Onuchic JN, Thirumalai D (1995) Navigating the folding routes. Science 267:1619CrossRefGoogle Scholar
  38. 38.
    Osterhout JJ, Baldwin RL, York EJ et al (1989) Proton NMR studies of the solution conformations of an analog of the C-peptide of ribonuclease A. Biochemistry 28:7059–7064CrossRefGoogle Scholar
  39. 39.
    Radhakrishnan I, Pérez-Alvarado GC, Parker D et al (1997) Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator: coactivator interactions. Cell 91:741–752CrossRefGoogle Scholar
  40. 40.
    Radhakrishnan I, Pérez-Alvarado GC, Dyson HJ et al (1998) Conformational preferences in the ser133-phosphorylated and non-phosphorylated forms of the kinase inducible transactivation domain of creb. FEBS Lett 430:317–322CrossRefGoogle Scholar
  41. 41.
    Mitchell M (1996) An introduction to genetic algorithms. MIT Press, CambridgeGoogle Scholar
  42. 42.
    Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092CrossRefGoogle Scholar
  43. 43.
    Cauchy A (1847) Méthode générale pour la résolution des systémes d’équations simultanées. C R Acad Sci Paris 25:536–538Google Scholar
  44. 44.
    Ooi T, Oobatake M, Némethy G et al (1987) Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. Proc Natl Acad Sci USA 84:3086–3090CrossRefGoogle Scholar
  45. 45.
    Eisenberg D, McLachlan AD (1986) Solvation energy in protein folding and binding. Nature 319:199–203CrossRefGoogle Scholar
  46. 46.
    van der Spoel D, Lindahl E, Hess B, et al (2010) Gromacs user manual, version 4.5. Sweden: Royal Institute of Technology and Uppsala University, Stockholm, UppsalaGoogle Scholar
  47. 47.
    Monticelli L, Sorin EJ, Tieleman DP et al (2008) Molecular simulation of multistate peptide dynamics: a comparison between microsecond timescale sampling and multiple shorter trajectories. J Comput Chem 29:1740–1752CrossRefGoogle Scholar
  48. 48.
    Hess B, Kutzner C, van der Spoel D et al (2008) Gromacs 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447CrossRefGoogle Scholar
  49. 49.
    Brown JE, Klee WA (1971) Helix-coil transition of the isolated amino terminus of ribonuclease. Biochemistry 10:470–476CrossRefGoogle Scholar
  50. 50.
    Shoemaker KR, Kim PS, York EJ et al (1987) Tests of the helix dipole model for stabilization of α-helices. Nature 326:563–567CrossRefGoogle Scholar
  51. 51.
    Timsit Y, Allemand F, Chiaruttini C et al (2006) Coexistence of two protein folding states in the crystal structure of ribosomal protein L20. EMBO Rep 7:1013–1018CrossRefGoogle Scholar
  52. 52.
    Chen HF (2009) Molecular dynamics simulation of phosphorylated KID post-translational modification. PLoS ONE 4:e6516CrossRefGoogle Scholar
  53. 53.
    Zor T, Mayr BM, Dyson HJ et al (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 277:42241–42248CrossRefGoogle Scholar
  54. 54.
    Li J, Zhang J, Ge W et al (2004) Multi-scale methodology for complex systems. Chem Eng Sci 59:1687–1700CrossRefGoogle Scholar
  55. 55.
    Ge W, Chen F, Gao J et al (2007) Analytical multi-scale method for multi-phase complex systems in process engineering–bridging reductionism and holism. Chem Eng Sci 62:3346–3377CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.State Key Laboratory of Multiphase Complex Systems, Institute of Process EngineeringChinese Academy of SciencesBeijingChina
  2. 2.University of Chinese Academy of SciencesBeijingChina

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