Solution to the Protein Folding Problem

  • Ariel Fernández
Part of the Soft and Biological Matter book series (SOBIMA)


This chapter unravels a first-principle solution to the protein folding problem. The solution incorporates the dynamic interplay between the formation of packing defects and the interfacial tension created by such defects. Thus, the solution symbiotically combines a structural and epistructural approach to compute the dynamic entanglement between protein chain and solvent. The structural perspective explores the concept of wrapping, its intimate relation to cooperativity and its bearing on the expediency and reproducibility of the folding process. Wrapping refers to the environmental enhancement of intramolecular electrostatic interactions through an exclusion of surrounding water that takes place as the chain folds onto itself. In this way a many-body picture of the folding process emerges whereby the folding chain interacts with itself and at the same time shapes the microenvironments that stabilize or destabilize the intramolecular interactions. This picture reflects a dynamic competition between chain folding and backbone hydration, where ultimately, backbone hydrogen bonds prevail through cooperative wrapping, upholding the picture that “folding is a struggle for the survival of backbone hydrogen bonds”.


Folding Process Interfacial Free Energy Folding Pathway Backbone Hydrogen Bond Folding Dynamic 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Anfinsen CB. Principles that govern the folding of protein chains. Science. 1973;181:223–30.ADSCrossRefGoogle Scholar
  2. 2.
    Fernández A, Sosnick TR, Colubri A. Dynamics of hydrogen-bond desolvation in folding proteins. J Mol Biol. 2002;321:659–75.CrossRefGoogle Scholar
  3. 3.
    Chandler D. Interfaces and the driving force of hydrophobic assembly. Nature. 2005;437:640–7.ADSCrossRefGoogle Scholar
  4. 4.
    Jewett A, Pande VS, Plaxco KW. Cooperativity, smooth energy landscapes and the origins of topology-dependent protein folding rates. J Mol Biol. 2003;326:247–53.CrossRefGoogle Scholar
  5. 5.
    Scalley-Kim M, Baker D. Characterization of the folding energy landscapes of computer generated proteins suggests high folding free energy barriers and cooperativity may be consequences of natural selection. J Mol Biol. 2004;338:573–83.CrossRefGoogle Scholar
  6. 6.
    Fernández A, Colubri A, Berry RS. Three-body correlations in protein folding: the origin of cooperativity. Phys A. 2002;307:235–59.CrossRefGoogle Scholar
  7. 7.
    Fernández A, Kostov K, Berry RS. From residue matching patterns to protein folding topographies: general model and bovine pancreatic trypsin inhibitor. Proc Natl Acad Sci U S A. 1999;96:12991–6.ADSCrossRefGoogle Scholar
  8. 8.
    Fernández A, Colubri A, Berry RS. Topology to geometry in protein folding: beta-lactoglobulin. Proc Natl Acad Sci U S A. 2000;97:14062–6.ADSCrossRefGoogle Scholar
  9. 9.
    Fernández A, Kardos J, Goto J. Protein folding: could hydrophobic collapse be coupled with hydrogen-bond formation? FEBS Lett. 2003;536:187–92.CrossRefGoogle Scholar
  10. 10.
    Fernández A. Conformation-dependent environments in folding proteins. J Chem Phys. 2001;114:2489–502.ADSCrossRefGoogle Scholar
  11. 11.
    Avbelj F, Baldwin RL. Role of backbone solvation and electrostatics in generating preferred peptide backbone conformations: distributions of phi. Proc Natl Acad Sci U S A. 2003;100:5742–7.ADSCrossRefGoogle Scholar
  12. 12.
    Fernández A. Keeping dry and crossing membranes. Nat Biotechnol. 2004;22:1081–4.CrossRefGoogle Scholar
  13. 13.
    Krantz BA, Moran LB, Kentsis A, Sosnick TR. D/H amide kinetic isotope effects reveal when hydrogen bonds form during protein folding. Nat Struct Biol. 2000;7:62–71.CrossRefGoogle Scholar
  14. 14.
    Plaxco KW, Simmons KT, Baker D. Contact order, transition state placement and the refolding rates of single domain proteins. J Mol Biol. 1998;277:985–94.CrossRefGoogle Scholar
  15. 15.
    Fersht A. Transition-state structure as a unifying basis in protein-folding mechanisms: contact order, chain topology, stability, and the extended nucleus mechanism. Proc Natl Acad Sci U S A. 2000;97:1525–929.ADSCrossRefGoogle Scholar
  16. 16.
    Fernández A, Scott LR. Adherence of packing defects in soluble proteins. Phys Rev Lett. 2003;91:018102.ADSCrossRefGoogle Scholar
  17. 17.
    Fernández A. What caliber pore is like a pipe? Nanotubes as modulators of ion gradients. J Chem Phys. 2003;119:5315–9.ADSCrossRefGoogle Scholar
  18. 18.
    Fernández A, Shen M, Colubri A, Sosnick TR, Freed KF. Large-scale context in protein folding: villin headpiece. Biochemistry. 2003;42:664–71.CrossRefGoogle Scholar
  19. 19.
    Duan Y, Kollman PA. Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. Science. 1998;282:740–4.ADSCrossRefGoogle Scholar
  20. 20.
    Baldwin RL. Making a network of hydrophobic clusters. Science. 2002;295:1657–8.CrossRefGoogle Scholar
  21. 21.
    Nemethy G, Steinberg IZ, Scheraga HA. The influence of water structure and hydrophobic contacts on the strength of side-chain hydrogen bonds in proteins. Biopolymers. 1963;1:43–69.CrossRefGoogle Scholar
  22. 22.
    Fernández A, Berry RS. Extent of hydrogen-bond protection in folded proteins: a constraint on packing architectures. Biophys J. 2002;83:2475–81.CrossRefGoogle Scholar
  23. 23.
    Novotny J, Bruccoleri R, Karplus M. Analysis of incorrectly folded protein models. Implications for structure predictions. J Mol Biol. 1984;177:787–818.CrossRefGoogle Scholar
  24. 24.
    Daggett V, Levitt M. A model of the molten globule state from molecular dynamics simulations. Proc Natl Acad Sci U S A. 1992;89:5142–6.ADSCrossRefGoogle Scholar
  25. 25.
    Brooks CL, Case D. Simulations of peptide conformational dynamics and thermodynamics. Chem Rev. 1993;93:2487–502.CrossRefGoogle Scholar
  26. 26.
    Fernández A, Rogale K. Sequence-space selection of cooperative model proteins. J Phys A Math Gen. 2004;37:197–202.MathSciNetCrossRefzbMATHGoogle Scholar
  27. 27.
    Kuwata K, Shastry R, Cheng H, Hoshino M, Batt CA, Goto Y, Roder H. Structural and kinetic characterization of early folding events in beta-lactoglobulin. Nat Struct Biol. 2001;8:151–5.CrossRefGoogle Scholar
  28. 28.
    Nymeyer H, Garcia AE, Onuchic JN. Folding funnels and frustration in off-lattice minimalist protein landscapes. Proc Natl Acad Sci. 1998;95:5921–8.ADSCrossRefGoogle Scholar
  29. 29.
    Onuchic JN, Luthey-Schulten Z, Wolynes PG. Theory of protein folding: the energy landscape perspective. Annu Rev Phys Chem. 1997;48:545–600.ADSCrossRefGoogle Scholar
  30. 30.
    Chan HS, Dill KA. From Levinthal to pathways to funnels. Nat Struct Biol. 1997;4:10–9.CrossRefGoogle Scholar
  31. 31.
    Fernández A, Colubri A, Berry RS. Topologies to geometries in protein folding: hierarchical and nonhierarchical scenarios. J Chem Phys. 2001;114:5871–88.ADSCrossRefGoogle Scholar
  32. 32.
    Shi Z, Krantz BA, Kallenbach N, Sosnick TR. Contribution of hydrogen bonding to protein stability estimated from isotope effects. Biochemistry. 2002;41:2120–9.CrossRefGoogle Scholar
  33. 33.
    Pietrosemoli N, Crespo A, Fernández A. Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res. 2007;6:3519–26.CrossRefGoogle Scholar
  34. 34.
    Schutz CN, Warshel A. What are the dielectric “constants” of proteins and how to validate electrostatic models? Proteins Struct Funct Gen. 2001;44:400–8.CrossRefGoogle Scholar
  35. 35.
    Fernández A. The principle of minimal episteric distortion of the water matrix and its steering role in protein folding. J Chem Phys. 2013;139:085101.ADSCrossRefGoogle Scholar
  36. 36.
    Fernández A. Fast track communication: water promotes the sealing of nanoscale packing defects in folding proteins. J Phys Condens Matter. 2014;26:202101.CrossRefGoogle Scholar
  37. 37.
    Salomon-Ferrer R, Case DA, Walker RC. An overview of the Amber biomolecular simulation package. WIREs Comput Mol Sci. 2013;3:198–210.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Ariel Fernández
    • 1
    • 2
  1. 1.National Research Council (CONICET)Buenos AiresArgentina
  2. 2.Rice UniversityHoustonUSA

Personalised recommendations