Conformational Entropy and Protein Stability

  • K. A. Dill
  • D. O. V. Alonso
Part of the Colloquium der Gesellschaft für Biologische Chemie 14.–16. April 1988 in Mosbach/Baden book series (MOSBACH, volume 39)


A principal driving force for the folding of a protein to its globular state is the tendency for the hydrophobic side chains of amino acids to cluster to avoid contact with the solvent (Kauzmann 1959). However, by itself hydrophobicity is too strong a driving force to account for the stabilities of proteins. An early estimate (Tanford 1962) suggested the hydrophobic interaction contributed the order of 180 kcal/mol toward condensation in myoglobin, but experiments (Tanford 1962; Pace 1975; Privalov and Kechinashuili 1974; Privalov 1979) show that free energies of folding are only about 1/10th as large. Hence, it is clear that there is at least one additional strong driving force in the opposite direction, toward the unfolded state, but with magnitude almost equal to that of the hydrophobic interaction. Thus, the marginal observed stabilities of globular proteins appear to be due to a small difference of large driving forces. The principal candidate for the opposing force is the conformational entropy: the conformational freedom of the molecule should clearly be greater in the many unfolded configurations than in the folded state. Statistical thermodynamic theory has recently been developed to account for this balance of forces (Dill 1985; Dill et al. 1988). Our purpose here is to focus on the role of the conformational entropy.


Chain Segment Hydrophobic Side Chain Conformational Entropy Conformational Freedom Segment Density 
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  1. Barber NM, Ninham DW (1988) Random and restricted walks. Gordon and Breach, New YorkGoogle Scholar
  2. Chan HS, Dill KA (1989) J Chem Phys (in press)Google Scholar
  3. Dill KA (1985) Biochemistry 24:1501PubMedCrossRefGoogle Scholar
  4. Dill KA, Alonso DOV, Hutchinson K (submitted)Google Scholar
  5. DiMarzio EA (1965) J Chem Phys 42:2101–2106CrossRefGoogle Scholar
  6. Feller W (1957) An introduction to probability theory and its application. Wiley, New YorkGoogle Scholar
  7. Flory PJ (1953) Principles of Polymer Chemistry. Cornell University PressGoogle Scholar
  8. Flory PJ (1969) Statistical mechanics of chain molecules. Wiley, New YorkGoogle Scholar
  9. Jacobson H, Stockmayer WH (1950) J Chem Phys 18:1600CrossRefGoogle Scholar
  10. Karplus M, Ichiye T, Pettit BM (1987) Biophys J 52:1083PubMedCrossRefGoogle Scholar
  11. Kauzmann W (1959) Adv Protein Chem 14:1PubMedCrossRefGoogle Scholar
  12. Matthews BW, Nicholson H, Becktel WJ (1987) Proc Natl Acad Sci USA 84:6663–6667PubMedCrossRefGoogle Scholar
  13. Mattice WL, Scheraga HA (1984) Biopolymers 23:1701–1724PubMedCrossRefGoogle Scholar
  14. Pace N (1975) CRC Crit Rev Biochem 3:1PubMedCrossRefGoogle Scholar
  15. Pace CN, Grimsley GR, Thomson JA, Barnett BJ J Biol Chem (submitted)Google Scholar
  16. Perry LJ, Wetzel R (1984) Science 226:555PubMedCrossRefGoogle Scholar
  17. Poland D, Scheraga H (1970) Theory of the helix-coil transitions in biopolymers. Academic Press, New YorkGoogle Scholar
  18. Privalov PL (1979) Adv Protein Chem 33:167PubMedCrossRefGoogle Scholar
  19. Privalov PL, Kechinashville NN (1974) J Mol Biol 86:665PubMedCrossRefGoogle Scholar
  20. Tanford C (1962) J Am Chem Soc 84:4240CrossRefGoogle Scholar
  21. Wetzel R (1987) Protein Engineering 1:79PubMedCrossRefGoogle Scholar
  22. Wells JA, Powers DB (1986) J Biol Chem 261:6564PubMedGoogle Scholar
  23. Zimm BH, Bragg JK (1959) J Chem Phys 31:526CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • K. A. Dill
  • D. O. V. Alonso
    • 1
  1. 1.Department of Pharmaceutical ChemistryUniversity of CaliforniaSan FranciscoUSA

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