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. 2000 Nov;9(11):2181–2191. doi: 10.1110/ps.9.11.2181

Free energy determinants of tertiary structure and the evaluation of protein models.

D Petrey 1, B Honig 1
PMCID: PMC2144503  PMID: 11152128

Abstract

We develop a protocol for estimating the free energy difference between different conformations of the same polypeptide chain. The conformational free energy evaluation combines the CHARMM force field with a continuum treatment of the solvent. In almost all cases studied, experimentally determined structures are predicted to be more stable than misfolded "decoys." This is due in part to the fact that the Coulomb energy of the native protein is consistently lower than that of the decoys. The solvation free energy generally favors the decoys, although the total electrostatic free energy (sum of Coulomb and solvation terms) favors the native structure. The behavior of the solvation free energy is somewhat counterintuitive and, surprisingly, is not correlated with differences in the burial of polar area between native structures and decoys. Rather. the effect is due to a more favorable charge distribution in the native protein, which, as is discussed, will tend to decrease its interaction with the solvent. Our results thus suggest, in keeping with a number of recent studies, that electrostatic interactions may play an important role in determining the native topology of a folded protein. On this basis, a simplified scoring function is derived that combines a Coulomb term with a hydrophobic contact term. This function performs as well as the more complete free energy evaluation in distinguishing the native structure from misfolded decoys. Its computational efficiency suggests that it can be used in protein structure prediction applications, and that it provides a physically well-defined alternative to statistically derived scoring functions.

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Selected References

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  1. Eisenberg D., McLachlan A. D. Solvation energy in protein folding and binding. Nature. 1986 Jan 16;319(6050):199–203. doi: 10.1038/319199a0. [DOI] [PubMed] [Google Scholar]
  2. Grimsley G. R., Shaw K. L., Fee L. R., Alston R. W., Huyghues-Despointes B. M., Thurlkill R. L., Scholtz J. M., Pace C. N. Increasing protein stability by altering long-range coulombic interactions. Protein Sci. 1999 Sep;8(9):1843–1849. doi: 10.1110/ps.8.9.1843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Holm L., Sander C. Evaluation of protein models by atomic solvation preference. J Mol Biol. 1992 May 5;225(1):93–105. doi: 10.1016/0022-2836(92)91028-n. [DOI] [PubMed] [Google Scholar]
  4. Huang E. S., Subbiah S., Levitt M. Recognizing native folds by the arrangement of hydrophobic and polar residues. J Mol Biol. 1995 Oct 6;252(5):709–720. doi: 10.1006/jmbi.1995.0529. [DOI] [PubMed] [Google Scholar]
  5. Janardhan A., Vajda S. Selecting near-native conformations in homology modeling: the role of molecular mechanics and solvation terms. Protein Sci. 1998 Aug;7(8):1772–1780. doi: 10.1002/pro.5560070812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Lazaridis T., Karplus M. Discrimination of the native from misfolded protein models with an energy function including implicit solvation. J Mol Biol. 1999 May 7;288(3):477–487. doi: 10.1006/jmbi.1999.2685. [DOI] [PubMed] [Google Scholar]
  7. Lazaridis T., Karplus M. Effective energy functions for protein structure prediction. Curr Opin Struct Biol. 2000 Apr;10(2):139–145. doi: 10.1016/s0959-440x(00)00063-4. [DOI] [PubMed] [Google Scholar]
  8. Mosimann S., Meleshko R., James M. N. A critical assessment of comparative molecular modeling of tertiary structures of proteins. Proteins. 1995 Nov;23(3):301–317. doi: 10.1002/prot.340230305. [DOI] [PubMed] [Google Scholar]
  9. Novotný J., Bruccoleri R., Karplus M. An analysis of incorrectly folded protein models. Implications for structure predictions. J Mol Biol. 1984 Aug 25;177(4):787–818. doi: 10.1016/0022-2836(84)90049-4. [DOI] [PubMed] [Google Scholar]
  10. Oliva M. T., Moult J. Local electrostatic optimization in proteins. Protein Eng. 1999 Sep;12(9):727–735. doi: 10.1093/protein/12.9.727. [DOI] [PubMed] [Google Scholar]
  11. Park B., Levitt M. Energy functions that discriminate X-ray and near native folds from well-constructed decoys. J Mol Biol. 1996 May 3;258(2):367–392. doi: 10.1006/jmbi.1996.0256. [DOI] [PubMed] [Google Scholar]
  12. Pickett S. D., Sternberg M. J. Empirical scale of side-chain conformational entropy in protein folding. J Mol Biol. 1993 Jun 5;231(3):825–839. doi: 10.1006/jmbi.1993.1329. [DOI] [PubMed] [Google Scholar]
  13. Sali A., Blundell T. L. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993 Dec 5;234(3):779–815. doi: 10.1006/jmbi.1993.1626. [DOI] [PubMed] [Google Scholar]
  14. Spassov V. Z., Karshikoff A. D., Ladenstein R. Optimization of the electrostatic interactions in proteins of different functional and folding type. Protein Sci. 1994 Sep;3(9):1556–1569. doi: 10.1002/pro.5560030921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Spassov V. Z., Ladenstein R., Karshikoff A. D. Optimization of the electrostatic interactions between ionized groups and peptide dipoles in proteins. Protein Sci. 1997 Jun;6(6):1190–1196. doi: 10.1002/pro.5560060607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Vorobjev Y. N., Almagro J. C., Hermans J. Discrimination between native and intentionally misfolded conformations of proteins: ES/IS, a new method for calculating conformational free energy that uses both dynamics simulations with an explicit solvent and an implicit solvent continuum model. Proteins. 1998 Sep 1;32(4):399–413. [PubMed] [Google Scholar]
  17. Wada A., Nakamura H. Nature of the charge distribution in proteins. Nature. 1981 Oct 29;293(5835):757–758. doi: 10.1038/293757a0. [DOI] [PubMed] [Google Scholar]
  18. Yang A. S., Hitz B., Honig B. Free energy determinants of secondary structure formation: III. beta-turns and their role in protein folding. J Mol Biol. 1996 Jun 21;259(4):873–882. doi: 10.1006/jmbi.1996.0364. [DOI] [PubMed] [Google Scholar]
  19. Yang A. S., Honig B. Free energy determinants of secondary structure formation: I. alpha-Helices. J Mol Biol. 1995 Sep 22;252(3):351–365. doi: 10.1006/jmbi.1995.0502. [DOI] [PubMed] [Google Scholar]
  20. Yang A. S., Honig B. Free energy determinants of secondary structure formation: II. Antiparallel beta-sheets. J Mol Biol. 1995 Sep 22;252(3):366–376. doi: 10.1006/jmbi.1995.0503. [DOI] [PubMed] [Google Scholar]

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