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. 2000 Apr;9(4):812–819. doi: 10.1110/ps.9.4.812

Scoring functions in protein folding and design.

R I Dima 1, J R Banavar 1, A Maritan 1
PMCID: PMC2144606  PMID: 10794424

Abstract

We present an analysis of the assumptions behind some of the most commonly used methods for evaluating the goodness of the fit between a sequence and a structure. Our studies on a lattice model show that methods based on statistical considerations are easy to use and can capture some of the features of protein-like sequences and their corresponding native states, but unfortunately are incapable of recognizing, with certainty, the native-like conformation of a sequence among a set of decoys. Meanwhile, an optimization method, entailing the determination of the parameters of an effective free energy of interaction, is much more reliable in recognizing the native state of a sequence. However, the statistical method is shown to perform quite well in tests of protein design.

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Selected References

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  1. Bernstein F. C., Koetzle T. F., Williams G. J., Meyer E. F., Jr, Brice M. D., Rodgers J. R., Kennard O., Shimanouchi T., Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. doi: 10.1016/s0022-2836(77)80200-3. [DOI] [PubMed] [Google Scholar]
  2. Betancourt M. R., Thirumalai D. Pair potentials for protein folding: choice of reference states and sensitivity of predicted native states to variations in the interaction schemes. Protein Sci. 1999 Feb;8(2):361–369. doi: 10.1110/ps.8.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bowie J. U., Lüthy R., Eisenberg D. A method to identify protein sequences that fold into a known three-dimensional structure. Science. 1991 Jul 12;253(5016):164–170. doi: 10.1126/science.1853201. [DOI] [PubMed] [Google Scholar]
  4. Bryant S. H., Lawrence C. E. An empirical energy function for threading protein sequence through the folding motif. Proteins. 1993 May;16(1):92–112. doi: 10.1002/prot.340160110. [DOI] [PubMed] [Google Scholar]
  5. Chiu T. L., Goldstein R. A. Optimizing energy potentials for success in protein tertiary structure prediction. Fold Des. 1998;3(3):223–228. doi: 10.1016/S1359-0278(98)00030-3. [DOI] [PubMed] [Google Scholar]
  6. Cordes M. H., Walsh N. P., McKnight C. J., Sauer R. T. Evolution of a protein fold in vitro. Science. 1999 Apr 9;284(5412):325–328. doi: 10.1126/science.284.5412.325. [DOI] [PubMed] [Google Scholar]
  7. Dalal S., Balasubramanian S., Regan L. Protein alchemy: changing beta-sheet into alpha-helix. Nat Struct Biol. 1997 Jul;4(7):548–552. doi: 10.1038/nsb0797-548. [DOI] [PubMed] [Google Scholar]
  8. Goldstein R. A., Luthey-Schulten Z. A., Wolynes P. G. Optimal protein-folding codes from spin-glass theory. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4918–4922. doi: 10.1073/pnas.89.11.4918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goldstein R. A., Luthey-Schulten Z. A., Wolynes P. G. Protein tertiary structure recognition using optimized Hamiltonians with local interactions. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9029–9033. doi: 10.1073/pnas.89.19.9029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hao M. H., Scheraga H. A. Designing potential energy functions for protein folding. Curr Opin Struct Biol. 1999 Apr;9(2):184–188. doi: 10.1016/s0959-440x(99)80026-8. [DOI] [PubMed] [Google Scholar]
  11. Hao M. H., Scheraga H. A. How optimization of potential functions affects protein folding. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4984–4989. doi: 10.1073/pnas.93.10.4984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hendlich M., Lackner P., Weitckus S., Floeckner H., Froschauer R., Gottsbacher K., Casari G., Sippl M. J. Identification of native protein folds amongst a large number of incorrect models. The calculation of low energy conformations from potentials of mean force. J Mol Biol. 1990 Nov 5;216(1):167–180. doi: 10.1016/S0022-2836(05)80068-3. [DOI] [PubMed] [Google Scholar]
  13. Jones D. T., Taylor W. R., Thornton J. M. A new approach to protein fold recognition. Nature. 1992 Jul 2;358(6381):86–89. doi: 10.1038/358086a0. [DOI] [PubMed] [Google Scholar]
  14. Kolinski A., Skolnick J. Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme. Proteins. 1994 Apr;18(4):338–352. doi: 10.1002/prot.340180405. [DOI] [PubMed] [Google Scholar]
  15. Koretke K. K., Luthey-Schulten Z., Wolynes P. G. Self-consistently optimized energy functions for protein structure prediction by molecular dynamics. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2932–2937. doi: 10.1073/pnas.95.6.2932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Koretke K. K., Luthey-Schulten Z., Wolynes P. G. Self-consistently optimized statistical mechanical energy functions for sequence structure alignment. Protein Sci. 1996 Jun;5(6):1043–1059. doi: 10.1002/pro.5560050607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Li H., Helling R., Tang C., Wingreen N. Emergence of preferred structures in a simple model of protein folding. Science. 1996 Aug 2;273(5275):666–669. doi: 10.1126/science.273.5275.666. [DOI] [PubMed] [Google Scholar]
  18. Lüthy R., Bowie J. U., Eisenberg D. Assessment of protein models with three-dimensional profiles. Nature. 1992 Mar 5;356(6364):83–85. doi: 10.1038/356083a0. [DOI] [PubMed] [Google Scholar]
  19. Maiorov V. N., Crippen G. M. Contact potential that recognizes the correct folding of globular proteins. J Mol Biol. 1992 Oct 5;227(3):876–888. doi: 10.1016/0022-2836(92)90228-c. [DOI] [PubMed] [Google Scholar]
  20. Mirny L. A., Shakhnovich E. I. How to derive a protein folding potential? A new approach to an old problem. J Mol Biol. 1996 Dec 20;264(5):1164–1179. doi: 10.1006/jmbi.1996.0704. [DOI] [PubMed] [Google Scholar]
  21. Miyazawa S., Jernigan R. L. Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. J Mol Biol. 1996 Mar 1;256(3):623–644. doi: 10.1006/jmbi.1996.0114. [DOI] [PubMed] [Google Scholar]
  22. Miyazawa S., Jernigan R. L. Self-consistent estimation of inter-residue protein contact energies based on an equilibrium mixture approximation of residues. Proteins. 1999 Jan 1;34(1):49–68. doi: 10.1002/(sici)1097-0134(19990101)34:1<49::aid-prot5>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Pellegrini M., Doniach S. Computer simulation of antibody binding specificity. Proteins. 1993 Apr;15(4):436–444. doi: 10.1002/prot.340150410. [DOI] [PubMed] [Google Scholar]
  25. Rooman M. J., Wodak S. J. Are database-derived potentials valid for scoring both forward and inverted protein folding? Protein Eng. 1995 Sep;8(9):849–858. doi: 10.1093/protein/8.9.849. [DOI] [PubMed] [Google Scholar]
  26. Seno F., Maritan A., Banavar J. R. Interaction potentials for protein folding. Proteins. 1998 Feb 15;30(3):244–248. doi: 10.1002/(sici)1097-0134(19980215)30:3<244::aid-prot4>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  27. Shakhnovich E., Abkevich V., Ptitsyn O. Conserved residues and the mechanism of protein folding. Nature. 1996 Jan 4;379(6560):96–98. doi: 10.1038/379096a0. [DOI] [PubMed] [Google Scholar]
  28. Simons K. T., Kooperberg C., Huang E., Baker D. Assembly of protein tertiary structures from fragments with similar local sequences using simulated annealing and Bayesian scoring functions. J Mol Biol. 1997 Apr 25;268(1):209–225. doi: 10.1006/jmbi.1997.0959. [DOI] [PubMed] [Google Scholar]
  29. Simons K. T., Ruczinski I., Kooperberg C., Fox B. A., Bystroff C., Baker D. Improved recognition of native-like protein structures using a combination of sequence-dependent and sequence-independent features of proteins. Proteins. 1999 Jan 1;34(1):82–95. doi: 10.1002/(sici)1097-0134(19990101)34:1<82::aid-prot7>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  30. Sippl M. J. Calculation of conformational ensembles from potentials of mean force. An approach to the knowledge-based prediction of local structures in globular proteins. J Mol Biol. 1990 Jun 20;213(4):859–883. doi: 10.1016/s0022-2836(05)80269-4. [DOI] [PubMed] [Google Scholar]
  31. Sippl M. J., Weitckus S. Detection of native-like models for amino acid sequences of unknown three-dimensional structure in a data base of known protein conformations. Proteins. 1992 Jul;13(3):258–271. doi: 10.1002/prot.340130308. [DOI] [PubMed] [Google Scholar]
  32. Skolnick J., Jaroszewski L., Kolinski A., Godzik A. Derivation and testing of pair potentials for protein folding. When is the quasichemical approximation correct? Protein Sci. 1997 Mar;6(3):676–688. doi: 10.1002/pro.5560060317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Skolnick J., Kolinski A. Simulations of the folding of a globular protein. Science. 1990 Nov 23;250(4984):1121–1125. doi: 10.1126/science.250.4984.1121. [DOI] [PubMed] [Google Scholar]
  34. Sun S. Reduced representation model of protein structure prediction: statistical potential and genetic algorithms. Protein Sci. 1993 May;2(5):762–785. doi: 10.1002/pro.5560020508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tanaka S., Scheraga H. A. Medium- and long-range interaction parameters between amino acids for predicting three-dimensional structures of proteins. Macromolecules. 1976 Nov-Dec;9(6):945–950. doi: 10.1021/ma60054a013. [DOI] [PubMed] [Google Scholar]
  36. Thomas P. D., Dill K. A. Statistical potentials extracted from protein structures: how accurate are they? J Mol Biol. 1996 Mar 29;257(2):457–469. doi: 10.1006/jmbi.1996.0175. [DOI] [PubMed] [Google Scholar]
  37. Wilmanns M., Eisenberg D. Three-dimensional profiles from residue-pair preferences: identification of sequences with beta/alpha-barrel fold. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1379–1383. doi: 10.1073/pnas.90.4.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wilson C., Doniach S. A computer model to dynamically simulate protein folding: studies with crambin. Proteins. 1989;6(2):193–209. doi: 10.1002/prot.340060208. [DOI] [PubMed] [Google Scholar]
  39. Zhang C. Extracting contact energies from protein structures: a study using a simplified model. Proteins. 1998 May 15;31(3):299–308. [PubMed] [Google Scholar]
  40. Zhang C., Vasmatzis G., Cornette J. L., DeLisi C. Determination of atomic desolvation energies from the structures of crystallized proteins. J Mol Biol. 1997 Apr 4;267(3):707–726. doi: 10.1006/jmbi.1996.0859. [DOI] [PubMed] [Google Scholar]
  41. Zhang L., Skolnick J. How do potentials derived from structural databases relate to "true" potentials? Protein Sci. 1998 Jan;7(1):112–122. doi: 10.1002/pro.5560070112. [DOI] [PMC free article] [PubMed] [Google Scholar]

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