Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Dec;83(6):3032–3038. doi: 10.1016/S0006-3495(02)75308-3

Validity of Gō models: comparison with a solvent-shielded empirical energy decomposition.

Emanuele Paci 1, Michele Vendruscolo 1, Martin Karplus 1
PMCID: PMC1302383  PMID: 12496075

Abstract

Do Gō-type model potentials provide a valid approach for studying protein folding? They have been widely used for this purpose because of their simplicity and the speed of simulations based on their use. The essential assumption in such models is that only contact interactions existing in the native state determine the energy surface of a polypeptide chain, even for non-native configurations sampled along folding trajectories. Here we use an all-atom molecular mechanics energy function to investigate the adequacy of Gō-type potentials. We show that, although the contact approximation is accurate, non-native contributions to the energy can be significant. The assumed relation between residue-residue interaction energies and the number of contacts between them is found to be only approximate. By contrast, individual residue energies correlate very well with the number of contacts. The results demonstrate that models based on the latter should give meaningful results (e.g., as used to interpret phi values), whereas those that depend on the former are only qualitative, at best.

Full Text

The Full Text of this article is available as a PDF (199.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alm E., Baker D. Prediction of protein-folding mechanisms from free-energy landscapes derived from native structures. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11305–11310. doi: 10.1073/pnas.96.20.11305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blanco F. J., Ortiz A. R., Serrano L. 1H and 15N NMR assignment and solution structure of the SH3 domain of spectrin: comparison of unrefined and refined structure sets with the crystal structure. J Biomol NMR. 1997 Jun;9(4):347–357. doi: 10.1023/a:1018330122908. [DOI] [PubMed] [Google Scholar]
  3. Bryngelson J. D., Onuchic J. N., Socci N. D., Wolynes P. G. Funnels, pathways, and the energy landscape of protein folding: a synthesis. Proteins. 1995 Mar;21(3):167–195. doi: 10.1002/prot.340210302. [DOI] [PubMed] [Google Scholar]
  4. Chan H. S., Dill K. A. Protein folding in the landscape perspective: chevron plots and non-Arrhenius kinetics. Proteins. 1998 Jan;30(1):2–33. doi: 10.1002/(sici)1097-0134(19980101)30:1<2::aid-prot2>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  5. Cota E., Hamill S. J., Fowler S. B., Clarke J. Two proteins with the same structure respond very differently to mutation: the role of plasticity in protein stability. J Mol Biol. 2000 Sep 22;302(3):713–725. doi: 10.1006/jmbi.2000.4053. [DOI] [PubMed] [Google Scholar]
  6. Dinner A. R., Sali A., Smith L. J., Dobson C. M., Karplus M. Understanding protein folding via free-energy surfaces from theory and experiment. Trends Biochem Sci. 2000 Jul;25(7):331–339. doi: 10.1016/s0968-0004(00)01610-8. [DOI] [PubMed] [Google Scholar]
  7. Dobson C. M. Protein misfolding, evolution and disease. Trends Biochem Sci. 1999 Sep;24(9):329–332. doi: 10.1016/s0968-0004(99)01445-0. [DOI] [PubMed] [Google Scholar]
  8. Dobson C. M. The structural basis of protein folding and its links with human disease. Philos Trans R Soc Lond B Biol Sci. 2001 Feb 28;356(1406):133–145. doi: 10.1098/rstb.2000.0758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Duan Y., Kollman P. A. Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. Science. 1998 Oct 23;282(5389):740–744. doi: 10.1126/science.282.5389.740. [DOI] [PubMed] [Google Scholar]
  10. Endicott J. A., Noble M. E., Garman E. F., Brown N., Rasmussen B., Nurse P., Johnson L. N. The crystal structure of p13suc1, a p34cdc2-interacting cell cycle control protein. EMBO J. 1995 Mar 1;14(5):1004–1014. doi: 10.1002/j.1460-2075.1995.tb07081.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Galzitskaya O. V., Finkelstein A. V. A theoretical search for folding/unfolding nuclei in three-dimensional protein structures. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11299–11304. doi: 10.1073/pnas.96.20.11299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. García-Sáez I., Reverter D., Vendrell J., Avilés F. X., Coll M. The three-dimensional structure of human procarboxypeptidase A2. Deciphering the basis of the inhibition, activation and intrinsic activity of the zymogen. EMBO J. 1997 Dec 1;16(23):6906–6913. doi: 10.1093/emboj/16.23.6906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Improta S., Politou A. S., Pastore A. Immunoglobulin-like modules from titin I-band: extensible components of muscle elasticity. Structure. 1996 Mar 15;4(3):323–337. doi: 10.1016/s0969-2126(96)00036-6. [DOI] [PubMed] [Google Scholar]
  14. Karplus M. The Levinthal paradox: yesterday and today. Fold Des. 1997;2(4):S69–S75. doi: 10.1016/s1359-0278(97)00067-9. [DOI] [PubMed] [Google Scholar]
  15. Lazaridis T., Karplus M. "New view" of protein folding reconciled with the old through multiple unfolding simulations. Science. 1997 Dec 12;278(5345):1928–1931. doi: 10.1126/science.278.5345.1928. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Leahy D. J., Hendrickson W. A., Aukhil I., Erickson H. P. Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein. Science. 1992 Nov 6;258(5084):987–991. doi: 10.1126/science.1279805. [DOI] [PubMed] [Google Scholar]
  18. Li A., Daggett V. Characterization of the transition state of protein unfolding by use of molecular dynamics: chymotrypsin inhibitor 2. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10430–10434. doi: 10.1073/pnas.91.22.10430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McPhalen C. A., James M. N. Crystal and molecular structure of the serine proteinase inhibitor CI-2 from barley seeds. Biochemistry. 1987 Jan 13;26(1):261–269. doi: 10.1021/bi00375a036. [DOI] [PubMed] [Google Scholar]
  20. Muñoz V., Eaton W. A. A simple model for calculating the kinetics of protein folding from three-dimensional structures. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11311–11316. doi: 10.1073/pnas.96.20.11311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Otzen D. E., Rheinnecker M., Fersht A. R. Structural factors contributing to the hydrophobic effect: the partly exposed hydrophobic minicore in chymotrypsin inhibitor 2. Biochemistry. 1995 Oct 10;34(40):13051–13058. doi: 10.1021/bi00040a016. [DOI] [PubMed] [Google Scholar]
  22. Ozkan S. B., Bahar I., Dill K. A. Transition states and the meaning of Phi-values in protein folding kinetics. Nat Struct Biol. 2001 Sep;8(9):765–769. doi: 10.1038/nsb0901-765. [DOI] [PubMed] [Google Scholar]
  23. Paci Emanuele, Vendruscolo Michele, Karplus Martin. Native and non-native interactions along protein folding and unfolding pathways. Proteins. 2002 May 15;47(3):379–392. doi: 10.1002/prot.10089. [DOI] [PubMed] [Google Scholar]
  24. Pastore A., Saudek V., Ramponi G., Williams R. J. Three-dimensional structure of acylphosphatase. Refinement and structure analysis. J Mol Biol. 1992 Mar 20;224(2):427–440. doi: 10.1016/0022-2836(92)91005-a. [DOI] [PubMed] [Google Scholar]
  25. Ren J., Stuart D. I., Acharya K. R. Alpha-lactalbumin possesses a distinct zinc binding site. J Biol Chem. 1993 Sep 15;268(26):19292–19298. [PubMed] [Google Scholar]
  26. Shimada J., Kussell E. L., Shakhnovich E. I. The folding thermodynamics and kinetics of crambin using an all-atom Monte Carlo simulation. J Mol Biol. 2001 Apr 20;308(1):79–95. doi: 10.1006/jmbi.2001.4586. [DOI] [PubMed] [Google Scholar]
  27. Takada S. Go-ing for the prediction of protein folding mechanisms. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11698–11700. doi: 10.1073/pnas.96.21.11698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Taketomi H., Ueda Y., Gō N. Studies on protein folding, unfolding and fluctuations by computer simulation. I. The effect of specific amino acid sequence represented by specific inter-unit interactions. Int J Pept Protein Res. 1975;7(6):445–459. [PubMed] [Google Scholar]
  29. Vendruscolo M., Paci E., Dobson C. M., Karplus M. Three key residues form a critical contact network in a protein folding transition state. Nature. 2001 Feb 1;409(6820):641–645. doi: 10.1038/35054591. [DOI] [PubMed] [Google Scholar]
  30. Xu J., Baase W. A., Baldwin E., Matthews B. W. The response of T4 lysozyme to large-to-small substitutions within the core and its relation to the hydrophobic effect. Protein Sci. 1998 Jan;7(1):158–177. doi: 10.1002/pro.5560070117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhou Y., Karplus M. Interpreting the folding kinetics of helical proteins. Nature. 1999 Sep 23;401(6751):400–403. doi: 10.1038/43937. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES