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Semiempirical Solution to the Protein Folding Problem Through a Combination of Structural and Epistructural Approaches

  • Ariel Fernández Stigliano
Chapter

Abstract

This chapter unravels a provisional solution to the protein folding problem. The solution requires a combination of structural and epistructural approaches to the problem. The structural approach focuses on the molecular basis of cooperativity. We explore the concept of protein wrapping, its intimate relation to cooperativity, and its bearing on the expediency of the folding process for single-domain natural proteins. As previously described, wrapping refers to the environmental modulation or protection of intramolecular electrostatic interactions through an exclusion of surrounding water that takes place as the chain folds onto itself. Thus, a special many-body picture of the folding process emerges where the folding chain interacts with itself and also shapes the microenvironments that stabilize or destabilize the intramolecular interactions. This picture reflects a competition between chain folding and backbone hydration leading to the prevalence of backbone hydrogen bonds through cooperative interactions. On the other hand, the epistructural analysis provides a crucial component to the free energy of structural assemblage: the reversible work required to span the protein–water interface. Failures of cooperativity, i.e., wrapping deficiencies known as dehydrons, generate interfacial tension which, in turn, promotes cooperativity, so that an underlying principle of interfacial energy minimization becomes operative. The interfacial contribution to the free energy complements and steers the many-body wrapping dynamics arising from the structure-centric analysis, leading to a semiempirical solution to the protein folding problem.

Keywords

Intramolecular Hydrogen Bond Folding Process Effective Permittivity Interfacial Free Energy Folding Pathway 
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.

References

  1. 1.
    Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223–230CrossRefPubMedGoogle Scholar
  2. 2.
    Fernández A, Sosnick TR, Colubri A (2002) Dynamics of hydrogen-bond desolvation in folding proteins. J Mol Biol 321:659–675CrossRefPubMedGoogle Scholar
  3. 3.
    Chandler D (2005) Interfaces and the driving force of hydrophobic assembly. Nature 437:640–647CrossRefPubMedGoogle Scholar
  4. 4.
    Jewett A, Pande VS, Plaxco KW (2003) Cooperativity, smooth energy landscapes and the origins of topology-dependent protein folding rates. J Mol Biol 326:247–253Google Scholar
  5. 5.
    Scalley-Kim M, Baker D (2004) 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 338:573–583CrossRefPubMedGoogle Scholar
  6. 6.
    Fernández A, Colubri A, Berry RS (2002) Three-body correlations in protein folding: the origin of cooperativity. Phys A 307:235–259CrossRefGoogle Scholar
  7. 7.
    Fernández A, Kostov K, Berry RS (1999) From residue matching patterns to protein folding topographies: general model and bovine pancreatic trypsin inhibitor. Proc Natl Acad Sci USA 96:12991–12996CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Fernández A, Colubri A, Berry RS (2000) Topology to geometry in protein folding: beta-lactoglobulin. Proc Natl Acad Sci USA 97:14062–14066Google Scholar
  9. 9.
    Fernández A, Kardos J, Goto J (2003) Protein folding: could hydrophobic collapse be coupled with hydrogen-bond formation? FEBS Lett 536:187–192CrossRefPubMedGoogle Scholar
  10. 10.
    Fernández A (2001) Conformation-dependent environments in folding proteins. J Chem Phys 114:2489–2502CrossRefGoogle Scholar
  11. 11.
    Avbelj F, Baldwin RL (2003) Role of backbone solvation and electrostatics in generating preferred peptide backbone conformations: distributions of phi. Proc Natl Acad Sci USA 100:5742–5747CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Fernández A (2004) Keeping dry and crossing membranes. Nat Biotech 22:1081–1084CrossRefGoogle Scholar
  13. 13.
    Krantz BA, Moran LB, Kentsis A, Sosnick TR (2000) D/H amide kinetic isotope effects reveal when hydrogen bonds form during protein folding. Nat Struct Biol 7:62–71CrossRefPubMedGoogle Scholar
  14. 14.
    Plaxco KW, Simmons KT, Baker D (1998) Contact order, transition state placement and the refolding rates of single domain proteins. J Mol Biol 277:985–994Google Scholar
  15. 15.
    Fersht A (2000) 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 USA 97:1525–1929CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Fernández A, Scott LR (2003) Adherence of packing defects in soluble proteins. Phys Rev Lett 91:018102CrossRefPubMedGoogle Scholar
  17. 17.
    Fernández A (2003) What caliber pore is like a pipe? Nanotubes as modulators of ion gradients. J Chem Phys 119:5315–5319CrossRefGoogle Scholar
  18. 18.
    Fernández A, Shen M, Colubri A, Sosnick TR, Freed KF (2003) Large-scale context in protein folding: villin headpiece. Biochemistry 42:664–671CrossRefPubMedGoogle Scholar
  19. 19.
    Duan Y, Kollman PA (1998) Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. Science 282:740–744CrossRefPubMedGoogle Scholar
  20. 20.
    Baldwin RL (2002) Making a network of hydrophobic clusters. Science 295:1657–1658CrossRefPubMedGoogle Scholar
  21. 21.
    Nemethy G, Steinberg IZ, Scheraga HA (1963) The influence of water structure and hydrophobic contacts on the strength of side-chain hydrogen bonds in proteins. Biopolymers 1:43–69CrossRefGoogle Scholar
  22. 22.
    Fernández A, Berry RS (2002) Extent of hydrogen-bond protection in folded proteins: a constraint on packing architectures. Biophys J 83:2475–2481CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Novotny J, Bruccoleri R, Karplus M (1984) Analysis of incorrectly folded protein models. Implications for structure predictions. J Mol Biol 177:787–818CrossRefPubMedGoogle Scholar
  24. 24.
    Daggett V, Levitt M (1992) A model of the molten globule state from molecular dynamics simulations. Proc Natl Acad Sci USA 89:5142–5146CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Brooks CL, Case D (1993) Simulations of peptide conformational dynamics and thermodynamics. Chem Rev 93:2487–2502CrossRefGoogle Scholar
  26. 26.
    Fernández A, Rogale K (2004) Sequence-space selection of cooperative model proteins. J Phys A: Math Gen 37:197–202CrossRefGoogle Scholar
  27. 27.
    Kuwata K, Shastry R, Cheng H, Hoshino M, Batt CA, Goto Y, Roder H (2001) Structural and kinetic characterization of early folding events in beta-lactoglobulin. Nature Struct Biol 8:151–155CrossRefPubMedGoogle Scholar
  28. 28.
    Nymeyer H, Garcia AE, Onuchic JN (1998) Folding funnels and frustration in off-lattice minimalist protein landscapes. Proc Natl Acad Sci 95:5921–5928CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Onuchic JN, Luthey-Schulten Z, Wolynes PG (1997) Theory of protein folding: the energy landscape perspective. Annu Rev Phys Chem 48:545–600CrossRefPubMedGoogle Scholar
  30. 30.
    Chan HS, Dill KA (1997) From Levinthal to pathways to funnels. Nat Struct Biol 4:10–19CrossRefPubMedGoogle Scholar
  31. 31.
    Fernández A, Colubri A, Berry RS (2001) Topologies to geometries in protein folding: hierarchical and nonhierarchical scenarios. J Chem Phys 114:5871–5888CrossRefGoogle Scholar
  32. 32.
    Shi Z, Krantz BA, Kallenbach N, Sosnick TR (2002) Contribution of hydrogen bonding to protein stability estimated from isotope effects. Biochemistry 41:2120–2129CrossRefPubMedGoogle Scholar
  33. 33.
    Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res 6:3519–3526CrossRefPubMedGoogle Scholar
  34. 34.
    Schutz CN, Warshel A (2001) What are the dielectric “constants” of proteins and how to validate electrostatic models? Proteins-Struct Funct Gen 44:400–408CrossRefGoogle Scholar
  35. 35.
    Fernández A (2013) The principle of minimal episteric distortion of the water matrix and its steering role in protein folding. J Chem Phys 139:085101CrossRefPubMedGoogle Scholar
  36. 36.
    Fernández A (2014) Fast track communication: water promotes the sealing of nanoscale packing defects in folding proteins. J Phys: Condens Matter 26:202101Google Scholar
  37. 37.
    Salomon-Ferrer R, Case DA, Walker RC (2013) An overview of the amber biomolecular simulation package. WIREs Comput Mol Sci 3:198–210CrossRefGoogle Scholar
  38. 38.
    Duan Y, Kollman PA (1998) Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. Science 282:740–744CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.National Research Council–CONICETBuenos AiresArgentina
  2. 2.Former Karl F. Hasselmann Endowed Chair Professor of BioengineeringRice UniversityHoustonUSA

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