Skip to main content
PMC home page
Protein Science : A Publication of the Protein Society logoLink to Protein Science : A Publication of the Protein Society
. 1998 Mar;7(3):649–666. doi: 10.1002/pro.5560070314

Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin.

L S Caves 1, J D Evanseck 1, M Karplus 1
PMCID: PMC2143962  PMID: 9541397

Abstract

Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory.

Full Text

The Full Text of this article is available as a PDF (2.8 MB).

Selected References

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

  1. Amadei A., Linssen A. B., de Groot B. L., van Aalten D. M., Berendsen H. J. An efficient method for sampling the essential subspace of proteins. J Biomol Struct Dyn. 1996 Feb;13(4):615–625. doi: 10.1080/07391102.1996.10508874. [DOI] [PubMed] [Google Scholar]
  2. Auffinger P., Westhof E. H-bond stability in the tRNA(Asp) anticodon hairpin: 3 ns of multiple molecular dynamics simulations. Biophys J. 1996 Aug;71(2):940–954. doi: 10.1016/S0006-3495(96)79298-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Auffinger P., Westhof E. RNA hydration: three nanoseconds of multiple molecular dynamics simulations of the solvated tRNA(Asp) anticodon hairpin. J Mol Biol. 1997 Jun 13;269(3):326–341. doi: 10.1006/jmbi.1997.1022. [DOI] [PubMed] [Google Scholar]
  4. Berendsen H. J. Bio-molecular dynamics comes of age. Science. 1996 Feb 16;271(5251):954–955. doi: 10.1126/science.271.5251.954. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Boczko E. M., Brooks C. L., 3rd First-principles calculation of the folding free energy of a three-helix bundle protein. Science. 1995 Jul 21;269(5222):393–396. doi: 10.1126/science.7618103. [DOI] [PubMed] [Google Scholar]
  7. Bonvin A. M., Rullmann J. A., Lamerichs R. M., Boelens R., Kaptein R. "Ensemble" iterative relaxation matrix approach: a new NMR refinement protocol applied to the solution structure of crambin. Proteins. 1993 Apr;15(4):385–400. doi: 10.1002/prot.340150406. [DOI] [PubMed] [Google Scholar]
  8. Brooks C. L., 3rd Methodological advances in molecular dynamics simulations of biological systems. Curr Opin Struct Biol. 1995 Apr;5(2):211–215. doi: 10.1016/0959-440x(95)80078-6. [DOI] [PubMed] [Google Scholar]
  9. Bruccoleri R. E., Karplus M. Conformational sampling using high-temperature molecular dynamics. Biopolymers. 1990 Dec;29(14):1847–1862. doi: 10.1002/bip.360291415. [DOI] [PubMed] [Google Scholar]
  10. Caspar D. L. Problems in simulating macromolecular movements. Structure. 1995 Apr 15;3(4):327–329. doi: 10.1016/s0969-2126(01)00163-0. [DOI] [PubMed] [Google Scholar]
  11. Cheatham T. E., 3rd, Kollman P. A. Observation of the A-DNA to B-DNA transition during unrestrained molecular dynamics in aqueous solution. J Mol Biol. 1996 Jun 14;259(3):434–444. doi: 10.1006/jmbi.1996.0330. [DOI] [PubMed] [Google Scholar]
  12. Clarage J. B., Romo T., Andrews B. K., Pettitt B. M., Phillips G. N., Jr A sampling problem in molecular dynamics simulations of macromolecules. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3288–3292. doi: 10.1073/pnas.92.8.3288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cooper A. Thermodynamic fluctuations in protein molecules. Proc Natl Acad Sci U S A. 1976 Aug;73(8):2740–2741. doi: 10.1073/pnas.73.8.2740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Daggett V., Levitt M. Realistic simulations of native-protein dynamics in solution and beyond. Annu Rev Biophys Biomol Struct. 1993;22:353–380. doi: 10.1146/annurev.bb.22.060193.002033. [DOI] [PubMed] [Google Scholar]
  15. Dauter Z., Lamzin V. S., Wilson K. S. Proteins at atomic resolution. Curr Opin Struct Biol. 1995 Dec;5(6):784–790. doi: 10.1016/0959-440x(95)80011-5. [DOI] [PubMed] [Google Scholar]
  16. Derreumaux P., Schlick T. Long timestep dynamics of peptides by the dynamics driver approach. Proteins. 1995 Apr;21(4):282–302. doi: 10.1002/prot.340210403. [DOI] [PubMed] [Google Scholar]
  17. Elber R., Karplus M. Multiple conformational states of proteins: a molecular dynamics analysis of myoglobin. Science. 1987 Jan 16;235(4786):318–321. doi: 10.1126/science.3798113. [DOI] [PubMed] [Google Scholar]
  18. Elofsson A., Nilsson L. How consistent are molecular dynamics simulations? Comparing structure and dynamics in reduced and oxidized Escherichia coli thioredoxin. J Mol Biol. 1993 Oct 20;233(4):766–780. doi: 10.1006/jmbi.1993.1551. [DOI] [PubMed] [Google Scholar]
  19. Frauenfelder H. Complexity in proteins. Nat Struct Biol. 1995 Oct;2(10):821–823. doi: 10.1038/nsb1095-821. [DOI] [PubMed] [Google Scholar]
  20. Frauenfelder H., Sligar S. G., Wolynes P. G. The energy landscapes and motions of proteins. Science. 1991 Dec 13;254(5038):1598–1603. doi: 10.1126/science.1749933. [DOI] [PubMed] [Google Scholar]
  21. García AE. Large-amplitude nonlinear motions in proteins. Phys Rev Lett. 1992 Apr 27;68(17):2696–2699. doi: 10.1103/PhysRevLett.68.2696. [DOI] [PubMed] [Google Scholar]
  22. Gerstein M., Lesk A. M., Chothia C. Structural mechanisms for domain movements in proteins. Biochemistry. 1994 Jun 7;33(22):6739–6749. doi: 10.1021/bi00188a001. [DOI] [PubMed] [Google Scholar]
  23. Hayward S., Kitao A., Go N. Harmonic and anharmonic aspects in the dynamics of BPTI: a normal mode analysis and principal component analysis. Protein Sci. 1994 Jun;3(6):936–943. doi: 10.1002/pro.5560030608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hayward S., Kitao A., Hirata F., Go N. Effect of solvent on collective motions in globular protein. J Mol Biol. 1993 Dec 20;234(4):1207–1217. doi: 10.1006/jmbi.1993.1671. [DOI] [PubMed] [Google Scholar]
  25. Hünenberger P. H., Mark A. E., van Gunsteren W. F. Fluctuation and cross-correlation analysis of protein motions observed in nanosecond molecular dynamics simulations. J Mol Biol. 1995 Sep 29;252(4):492–503. doi: 10.1006/jmbi.1995.0514. [DOI] [PubMed] [Google Scholar]
  26. Ichiye T., Karplus M. Anisotropy and anharmonicity of atomic fluctuations in proteins: analysis of a molecular dynamics simulation. Proteins. 1987;2(3):236–259. doi: 10.1002/prot.340020308. [DOI] [PubMed] [Google Scholar]
  27. Ichiye T., Karplus M. Anisotropy and anharmonicity of atomic fluctuations in proteins: implications for X-ray analysis. Biochemistry. 1988 May 3;27(9):3487–3497. doi: 10.1021/bi00409a054. [DOI] [PubMed] [Google Scholar]
  28. Karplus M., Petsko G. A. Molecular dynamics simulations in biology. Nature. 1990 Oct 18;347(6294):631–639. doi: 10.1038/347631a0. [DOI] [PubMed] [Google Scholar]
  29. Kuczera K., Kuriyan J., Karplus M. Temperature dependence of the structure and dynamics of myoglobin. A simulation approach. J Mol Biol. 1990 May 20;213(2):351–373. doi: 10.1016/S0022-2836(05)80196-2. [DOI] [PubMed] [Google Scholar]
  30. Levitt M., Sharon R. Accurate simulation of protein dynamics in solution. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7557–7561. doi: 10.1073/pnas.85.20.7557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Louise-May S., Auffinger P., Westhof E. Calculations of nucleic acid conformations. Curr Opin Struct Biol. 1996 Jun;6(3):289–298. doi: 10.1016/s0959-440x(96)80046-7. [DOI] [PubMed] [Google Scholar]
  32. Mao B. Mass-weighted molecular dynamics simulation and conformational analysis of polypeptide. Biophys J. 1991 Sep;60(3):611–622. doi: 10.1016/S0006-3495(91)82090-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Noguti T., Go N. Structural basis of hierarchical multiple substates of a protein. I: Introduction. Proteins. 1989;5(2):97–103. doi: 10.1002/prot.340050203. [DOI] [PubMed] [Google Scholar]
  34. Ornstein R. L. Using molecular dynamics simulations on crambin to evaluate the suitability of different continuum dielectric and hydrogen atom models for protein simulations. J Biomol Struct Dyn. 1990 Apr;7(5):1019–1041. doi: 10.1080/07391102.1990.10508543. [DOI] [PubMed] [Google Scholar]
  35. Perutz M. F. Mechanisms of cooperativity and allosteric regulation in proteins. Q Rev Biophys. 1989 May;22(2):139–237. doi: 10.1017/s0033583500003826. [DOI] [PubMed] [Google Scholar]
  36. Petsko G. A. Not just your average structures. Nat Struct Biol. 1996 Jul;3(7):565–566. doi: 10.1038/nsb0796-565. [DOI] [PubMed] [Google Scholar]
  37. Post C. B., Brooks B. R., Karplus M., Dobson C. M., Artymiuk P. J., Cheetham J. C., Phillips D. C. Molecular dynamics simulations of native and substrate-bound lysozyme. A study of the average structures and atomic fluctuations. J Mol Biol. 1986 Aug 5;190(3):455–479. doi: 10.1016/0022-2836(86)90015-x. [DOI] [PubMed] [Google Scholar]
  38. Ringe D., Petsko G. A. Mapping protein dynamics by X-ray diffraction. Prog Biophys Mol Biol. 1985;45(3):197–235. doi: 10.1016/0079-6107(85)90002-1. [DOI] [PubMed] [Google Scholar]
  39. Schiffer C. A., van Gunsteren W. F. Structural stability of disulfide mutants of basic pancreatic trypsin inhibitor: a molecular dynamics study. Proteins. 1996 Sep;26(1):66–71. doi: 10.1002/(SICI)1097-0134(199609)26:1<66::AID-PROT6>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  40. Steinbach P. J., Ansari A., Berendzen J., Braunstein D., Chu K., Cowen B. R., Ehrenstein D., Frauenfelder H., Johnson J. B., Lamb D. C. Ligand binding to heme proteins: connection between dynamics and function. Biochemistry. 1991 Apr 23;30(16):3988–4001. doi: 10.1021/bi00230a026. [DOI] [PubMed] [Google Scholar]
  41. Stillinger F. H., Weber T. A. Packing structures and transitions in liquids and solids. Science. 1984 Sep 7;225(4666):983–989. doi: 10.1126/science.225.4666.983. [DOI] [PubMed] [Google Scholar]
  42. Straub J. E., Thirumalai D. Theoretical probes of conformational fluctuations in S-peptide and RNase A/3'-UMP enzyme product complex. Proteins. 1993 Apr;15(4):360–373. doi: 10.1002/prot.340150404. [DOI] [PubMed] [Google Scholar]
  43. Tidor B., Karplus M. The contribution of cross-links to protein stability: a normal mode analysis of the configurational entropy of the native state. Proteins. 1993 Jan;15(1):71–79. doi: 10.1002/prot.340150109. [DOI] [PubMed] [Google Scholar]
  44. Troyer J. M., Cohen F. E. Protein conformational landscapes: energy minimization and clustering of a long molecular dynamics trajectory. Proteins. 1995 Sep;23(1):97–110. doi: 10.1002/prot.340230111. [DOI] [PubMed] [Google Scholar]
  45. Yasri A., Chiche L., Haiech J., Grassy G. Rational choice of molecular dynamics simulation parameters through the use of the three-dimensional autocorrelation method: application to calmodulin flexibility study. Protein Eng. 1996 Nov;9(11):959–976. doi: 10.1093/protein/9.11.959. [DOI] [PubMed] [Google Scholar]
  46. de Groot B. L., Amadei A., Scheek R. M., van Nuland N. A., Berendsen H. J. An extended sampling of the configurational space of HPr from E. coli. Proteins. 1996 Nov;26(3):314–322. doi: 10.1002/(SICI)1097-0134(199611)26:3<314::AID-PROT7>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]

Articles from Protein Science : A Publication of the Protein Society are provided here courtesy of The Protein Society

RESOURCES