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PMID: 10639131 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Landscape approaches for determining the ensemble of folding transition states: success and failure hinge on the degree of frustration.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 2 ·2000-01-18 ·Pages 634-9

Nymeyer H, Socci ND, Onuchic JN

Abstract

We present a method for determining structural properties of the ensemble of folding transition states from protein simulations. This method relies on thermodynamic quantities (free energies as a function of global reaction coordinates, such as the percentage of native contacts) and not on "kinetic" measurements (rates, transmission coefficients, complete trajectories); consequently, it requires fewer computational resources compared with other approaches, making it more suited to large and complex models. We explain the theoretical framework that underlies this method and use it to clarify the connection between the experimentally determined Phi value, a quantity determined by the ratio of rate and stability changes due to point mutations, and the average structure of the transition state ensemble. To determine the accuracy of this thermodynamic approach, we apply it to minimalist protein models and compare these results with the ones obtained by using the standard experimental procedure for determining Phi values. We show that the accuracy of both methods depends sensitively on the amount of frustration. In particular, the results are similar when applied to models with minimal amounts of frustration, characteristic of rapid-folding, single-domain globular proteins.

MeSH Terms
Kinetics Models, Chemical Mutation Protein Folding Proteins/chemistry,genetics Thermodynamics
Chemicals
Proteins
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Nymeyer H
Department of Physics, University of California at San Diego, La Jolla, CA 92093-0319, USA. hnymeyer@ucsd.edu
Socci N D
Onuchic J N
References (48)
48 references, click to expand
  1. Protein folding mechanisms and the multidimensional folding funnel.
    Proteins. 1998 Aug 1;32(2):136-58 PMID: 9714155
  2. Molecular picture of folding of a small alpha/beta protein.
    Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1562-7 PMID: 9465055
  3. Obligatory steps in protein folding and the conformational diversity of the transition state.
    Nat Struct Biol. 1998 Aug;5(8):721-9 PMID: 9699637
  4. The kinetic folding intermediate of ribonuclease H resembles the acid molten globule and partially unfolded molecules detected under native conditions.
    Nat Struct Biol. 1997 Apr;4(4):298-304 PMID: 9095198
  5. Intermediates in the folding reactions of small proteins.
    Annu Rev Biochem. 1990;59:631-60 PMID: 2197986
  6. Structure of the transition state for folding of a protein derived from experiment and simulation.
    J Mol Biol. 1996 Mar 29;257(2):430-40 PMID: 8609634
  7. Time-resolved biophysical methods in the study of protein folding.
    Curr Opin Struct Biol. 1996 Oct;6(5):630-6 PMID: 8913685
  8. Submillisecond kinetics of protein folding.
    Curr Opin Struct Biol. 1997 Feb;7(1):10-4 PMID: 9032067
  9. Observation of distinct nanosecond and microsecond protein folding events.
    Nat Struct Biol. 1996 Nov;3(11):923-6 PMID: 8901868
  10. Kinetic mechanism of cytochrome c folding: involvement of the heme and its ligands.
    Biochemistry. 1994 Jun 7;33(22):6925-35 PMID: 8204626
  11. Pathways of protein folding.
    Annu Rev Biochem. 1993;62:653-83 PMID: 8352599
  12. Structure of the transition state in the folding process of human procarboxypeptidase A2 activation domain.
    J Mol Biol. 1998 Nov 13;283(5):1027-36 PMID: 9799641
  13. Spin glasses and the statistical mechanics of protein folding.
    Proc Natl Acad Sci U S A. 1987 Nov;84(21):7524-8 PMID: 3478708
  14. Toward an outline of the topography of a realistic protein-folding funnel.
    Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3626-30 PMID: 7724609
  15. First-principles calculation of the folding free energy of a three-helix bundle protein.
    Science. 1995 Jul 21;269(5222):393-6 PMID: 7618103
  16. Mapping the transition state and pathway of protein folding by protein engineering.
    Nature. 1989 Jul 13;340(6229):122-6 PMID: 2739734
  17. Exploring the folding free energy surface of a three-helix bundle protein.
    Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10161-6 PMID: 9294180
  18. Cytochrome c folding triggered by electron transfer.
    Chem Biol. 1996 Jun;3(6):491-7 PMID: 8807879
  19. Ultrafast thermally induced unfolding of RNase A.
    Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7292-6 PMID: 7638183
  20. Protein design: a perspective from simple tractable models
    Fold Des. 1998;3(3):R45-58 PMID: 9562552
  21. Molecular collapse: the rate-limiting step in two-state cytochrome c folding.
    Proteins. 1996 Apr;24(4):413-26 PMID: 9162942
  22. Folding pathway of a lattice model for proteins.
    Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1273-8 PMID: 9990014
  23. The folding of an enzyme. I. Theory of protein engineering analysis of stability and pathway of protein folding.
    J Mol Biol. 1992 Apr 5;224(3):771-82 PMID: 1569556
  24. The energy landscape of a fast-folding protein mapped by Ala-->Gly substitutions.
    Nat Struct Biol. 1997 Apr;4(4):305-10 PMID: 9095199
  25. Important role of hydrogen bonds in the structurally polarized transition state for folding of the src SH3 domain.
    Nat Struct Biol. 1998 Aug;5(8):714-20 PMID: 9699636
  26. Diffusion-limited contact formation in unfolded cytochrome c: estimating the maximum rate of protein folding.
    Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11615-7 PMID: 8876184
  27. Lattice models for proteins reveal multiple folding nuclei for nucleation-collapse mechanism.
    J Mol Biol. 1998 Sep 18;282(2):471-92 PMID: 9735420
  28. From Levinthal to pathways to funnels.
    Nat Struct Biol. 1997 Jan;4(1):10-9 PMID: 8989315
  29. Protein folding funnels: a kinetic approach to the sequence-structure relationship.
    Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8721-5 PMID: 1528885
  30. Movement of the position of the transition state in protein folding.
    Biochemistry. 1995 Oct 17;34(41):13656-62 PMID: 7577956
  31. Molten globular characteristics of the native state of apomyoglobin.
    Nat Struct Biol. 1994 Jul;1(7):447-52 PMID: 7664063
  32. Funnels, pathways, and the energy landscape of protein folding: a synthesis.
    Proteins. 1995 Mar;21(3):167-95 PMID: 7784423
  33. Nucleation mechanisms in protein folding.
    Curr Opin Struct Biol. 1997 Feb;7(1):3-9 PMID: 9032066
  34. Protein folding triggered by electron transfer.
    Science. 1996 Mar 15;271(5255):1558-60 PMID: 8599112
  35. Sequence space, folding and protein design.
    Curr Opin Struct Biol. 1996 Feb;6(1):3-10 PMID: 8696970
  36. Protein folding funnels: the nature of the transition state ensemble.
    Fold Des. 1996;1(6):441-50 PMID: 9080190
  37. Formation of a molten globule intermediate early in the kinetic folding pathway of apomyoglobin.
    Science. 1993 Nov 5;262(5135):892-6 PMID: 8235610
  38. Functional rapidly folding proteins from simplified amino acid sequences.
    Nat Struct Biol. 1997 Oct;4(10):805-9 PMID: 9334745
  39. Synergy between simulation and experiment in describing the energy landscape of protein folding.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8473-8 PMID: 9671702
  40. The changing nature of the protein folding transition state: implications for the shape of the free-energy profile for folding.
    J Mol Biol. 1998 Apr 10;277(4):933-43 PMID: 9545382
  41. Folding funnels and frustration in off-lattice minimalist protein landscapes.
    Proc Natl Acad Sci U S A. 1998 May 26;95(11):5921-8 PMID: 9600893
  42. The energy landscape theory of protein folding: insights into folding mechanisms and scenarios.
    Adv Protein Chem. 2000;53:87-152 PMID: 10751944
  43. Exploring the origins of topological frustration: design of a minimally frustrated model of fragment B of protein A.
    Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12512-7 PMID: 10535953
  44. Protein folding studied using hydrogen-exchange labeling and two-dimensional NMR.
    Annu Rev Biophys Biomol Struct. 1992;21:243-65 PMID: 1525469
  45. Theory of protein folding: the energy landscape perspective.
    Annu Rev Phys Chem. 1997;48:545-600 PMID: 9348663
  46. Fast events in protein folding: helix melting and formation in a small peptide.
    Biochemistry. 1996 Jan 23;35(3):691-7 PMID: 8547249
  47. "New view" of protein folding reconciled with the old through multiple unfolding simulations.
    Science. 1997 Dec 12;278(5345):1928-31 PMID: 9395391
  48. Monte Carlo-minimization approach to the multiple-minima problem in protein folding.
    Proc Natl Acad Sci U S A. 1987 Oct;84(19):6611-5 PMID: 3477791
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.97.2.634
Email
hnymeyer@ucsd.edu
Published
2000-01-18
Pages
634-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15382
Subset
IM
Grants
NIGMS NIH HHS · T32 GM008326 · United States
PHS HHS · T32 GN08326 · United States
External Links
PubMed source DOI: 10.1073/pnas.97.2.634 PMC Full Text View journal details
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