Computer Simulations of Protein-DNA Interactions

  • Mats Eriksson
  • Lennart Nilsson
Chapter

Abstract

Molecular recognition is an essential component in almost all biomolecular processes, specifically in processes relating to transcription and translation of the genetic material. Much progress has been made in recent years towards characterizing several such systems in structural terms, providing insight into the fundamental issue of the structural basis for sequence dependent interactions and binding; in particular one can identify some principles of recognition and structural organization within the transcription factor families (Pabo & Sauer, 1992). Molecular dynamics (MD) simulation provides a very detailed, structural and dynamic, description of biomolecular systems; this level of detail, which is very difficult to obtain by other means, is very valuable for a thorough understanding of the subtle balance between competing interactions involved in molecular recognition processes. From a comparison (Elofsson et al.,1993) of calculated interaction energies (enthalpies) in substrate:protein complexes, with calculated free energy values as well as with experimental data, it is quite clear that straightforward, intuitive guesses of the outcome of mutation experiments in complicated systems are unreliable. The influences of slight structural changes, interplay with solvent and ions, and entropic effects are very difficult to guess; more precise methods, like free energy perturbation or potential of mean force calculations, therefore are necessary. Although some aspects of these system may also require combined molecular mechanics/quantum mechanics energy calculations, the non-covalent binding processes that are the focus of this report have been studied using classical mechanics and empirical energy functions.

Keywords

Molecular Dynamics Simulation Glucocorticoid Receptor Estrogen Response Element Glucocorticoid Response Element Free Energy Perturbation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. Beveridge, D. & Ravishanker, G. (1994) Molecular Dynamics Studies of DNA, Curr. Op. Struct. Biol. 4, 246–255.CrossRefGoogle Scholar
  2. Beveridge, D.L. & DiCapua, F.M. (1994) Free Energy via Molecular Simulation: Applications to Chemical and Biochemical Systems, Ann. Rev. Biophys. Biophys. Chem. 18, 431–492CrossRefGoogle Scholar
  3. Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. & Karplus, M. (1983). CHARMM: A Program for Macromolecular Energy, Minimization and Dynamics Calculations. J. Comp. Chem. 4, 187–217.CrossRefGoogle Scholar
  4. Brooks, C.L, Karplus, M. & Pettitt, B.M. (1988) Proteins: A Theoretical Perspective of Dynamics, Structure and Thermodynamics. Adv. In Chem. Phys. Vol 71, Wiley, New York.Google Scholar
  5. Elofsson, A. & Nilsson, L. (1993) Free Energy Perturbations in Ribonuclease T1 Substrate Binding. A Study of the Influence of Simulation Length, Internal Degrees of Freedom and Structure in Free Energy Perturbations, Mol. Sim. 10, 255–276.CrossRefGoogle Scholar
  6. Elofsson, A., Kulinski, T., Rigler, R. & Nilsson, L. (1993) Site Specific Point Mutation Changes Specificity. A Molecular Modelling Study by Free Energy Simulations and Enzyme Kinetics of the Thermodynamics in Ribonuclease T1 Substrate Interactions, PROTEINS 17, 161–175PubMedCrossRefGoogle Scholar
  7. Eriksson, M., Berglund, H., Härd, T. & Nilsson, L. (1993) A Comparison of 15N NMR Relaxation Measurements with a Molecular Dynamics Simulation: Backbone Dynamics of the Glucocorticoid Receptor DNA-binding Domain, PROTEINS, 17, 375–390.PubMedCrossRefGoogle Scholar
  8. Eriksson, M.A.L., Härd, T. & Nilsson, L. (1994) Molecular Dynamics Simulation of a DNA Binding Protein Free and in Complex with DNA, in “Computational Approaches to Supramolecular Chemistry” (Ed. G. Wipff), NATO ASI Series, Kluwer, Dordrecht, pp 441–456CrossRefGoogle Scholar
  9. Eriksson, M.A.L., Härd, T. & Nilsson, L. (1995) Molecular Dynamics Simulations of the DNA -Binding Domain of the Glucocorticoid Receptor as a Dimer in Complex with DNA and as a Monomer in Solution, Biophys. J. 68, 402–426PubMedCrossRefGoogle Scholar
  10. Eriksson, M.A.L. & Nilsson, L. (1995) Structure, Thermodynamics and Cooperativity of the Glucocorticoid Receptor DNA-binding Domain in Complex with Different Response Elements, J. Mol. Biol. 253, 453–472.PubMedCrossRefGoogle Scholar
  11. Hard, T. & Nilsson, L. (1992) Free Energy Calculations Predict Sequence Specificity in DNA-Drug Complexes, Nucleosides & Nucleotides 11,167–173.CrossRefGoogle Scholar
  12. Kraulis, P.J. (1991) MOLSCRIPT: A Program to Produce Both Detailed and Schematic Plots of Protein Structure, J. Appl. Crystallogr. 24, 946–950.CrossRefGoogle Scholar
  13. Levitt, M. & Park, B.H. (1993) Water: now you see it now you don’t, Structure 1, 223–226.PubMedCrossRefGoogle Scholar
  14. Luisi B.F., Xu W.X., Otwinowski Z., Freedman L.P., Yamamoto K.R. and Sigler P.B., Nature Vol. 352 (1991) 497–505.PubMedCrossRefGoogle Scholar
  15. MacKerell, A.D., Rigler, R., Nilsson, L., Hahn, U. & Saenger, W. (1987). Biophysical Chemistry, 26, 247–261.PubMedCrossRefGoogle Scholar
  16. MacKerell, A.D., Nilsson,L., Rigler, R. & Saenger, W. (1988a) Biochemistry, 27, 4547–4556.CrossRefGoogle Scholar
  17. MacKerell, A.D., Rigler, R. Nilsson, L., Heinemann, U. & Saenger,W. (1988b). Eur. Biophys. J. 16, 287–297.CrossRefGoogle Scholar
  18. MacKerell, A.D., Nilsson, L., Rigler, R., Heinemann, U. & Saenger, W. (1989). Molecular Dynamics Simulations of Ribonuclease Tl: Comparison of the Free Enzyme and the 2’GMP-Enzyme Complex, Proteins 6, 20–31.PubMedCrossRefGoogle Scholar
  19. MacKerell Jr., A.D., Bashford, D., Bellott, M., Dunbrack Jr., R.L., Field, M.J., Fischer, S., Gao, J., Guo, H., Ha, S., Joseph, D., Kuchnir, L., Kuczera, K., Lau, F.T.K., Mattos, C., Michnick, S., Ngo, T., Nguyen, D.T., Prodhom, B., Roux, B., Schlenkrich, M., Smith., J.C., Stote, R., Straub, J. Wiorkiewicz-Kuczera, J. and Karplus, M. (1992) Self-consistent parameterization of biomolecules for molecular modeling and condensed phase simulations. FASEB Journal, 6:A143.Google Scholar
  20. MacKerell Jr., A.D., Wiorkiewicz-Kuczera, J. and Karplus, M. (1995) An all-atom empirical energy function for the simulation of nucleic acids, Journal of the American Chemical Society 117,11946–11975.CrossRefGoogle Scholar
  21. Nilges, M., Clore, G.M., Gronenborn, A.M., Brünger, A.T., Karplus, M. & Nilsson, L. (1987).The Three-Dimen-sional Solution Structure of the DNA Hexamer 5’d(GCATGC)Z. Combined Use of Nuclear Magnetic-Reso-nance and Restrained Molecular Dynamics. Biochemistry, 26, 3718–3733.PubMedCrossRefGoogle Scholar
  22. Nilsson, L. & Karplus, M. (1986). Molecular Dynamics Simulation of the Anticodon Arm of Phenylalanine Transfer RNA. In “Structure and Dynamics of RNA”, NATO ASI series A Vol. 110 (Eds. Hilbers, C.W. & van Knippenberg, P.), Plenum Press, New York,.151–159.CrossRefGoogle Scholar
  23. Norberg, J. & Nilsson, L. (1995a) Stacking Free Energy Profiles for All 16 Natural Diribonucleoside Monophosphates in Aqueous Solution, J. Am. Chem. Soc. 117, 10832–10840CrossRefGoogle Scholar
  24. Norberg, J. & Nilsson, L. (1995b) Temperature Dependence of the Stacking Propensity of Adenylyl-3’,5’-Adenosine, J. Phys. Chem. 99, 3056–3058.CrossRefGoogle Scholar
  25. Norberg, J. & Nilsson, L. (1995c) NMR Relaxation Times, Dynamics and Hydration of a Nucleic Acid Fragment from Molecular Dynamics Simulations, J. Phys. Chem. 99, 14876–14884.CrossRefGoogle Scholar
  26. Nordfund, T.M., Andersson,S.,Nilsson, L., Rigler, R., Gräslund, A. & McLaughlin, L.W. (1989). Structure and Dynamics of a Fluorescent DNA Oligomer Containing the EcoRI Recognition Sequence: Fluorescence, NMR and Molecular Dynamics Studies. Biochemistry 28, 9095–9103.CrossRefGoogle Scholar
  27. Pabo, C. & Sauer, R.T. (1992) Transcription factors: Structural families and principles of recognition. Ann. Rev. Bioch. 61, 1053–1095.CrossRefGoogle Scholar
  28. Robinson, C.R. & Sligar, S.C. (1993) J. Mol. Biol. 234, 302–306.PubMedCrossRefGoogle Scholar
  29. Schwabe, J.W.R., Chapman, L., Finch, J.T. & Rhodes, D. (1993) The crystal ‘structure of the oestrogen receptor DNA-binding domain bound to DNA: How receptors discriminate between their response elements. Cell 75, 567–578.PubMedCrossRefGoogle Scholar
  30. Zilliacus, J., Dahlman-Wright, K., Wright, A., Gustafsson, J.- Å. Carlstedt-Duke, J. (1991) DNA binding specificity of mutant glucocorticoid recptor DNA-binding domains, J. Biol. Chem. 266, 3101–3106.PubMedGoogle Scholar
  31. Zilliacus, J., Wright, A.P.H., Norinder, U., Gustafsson, J.-Å. & Carlstedt-Duke, J. (1992) Determinants for DNA Binding Site Recognition by the Glucocorticoid Receptor, J. Biol. Chem. 267, 24941–24947.PubMedGoogle Scholar
  32. Zilliacus, J., Wright, A.P.H., Carlstedt-Duke, J., Nilsson, L. & Gustafsson, J.-Å. (1995) Modulation of DNA Binding Specificity Within the Nuclear Receptor Family by Substitutions at a Single Amino Acid Position, PROTEINS 21, 57–67.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Mats Eriksson
    • 1
  • Lennart Nilsson
    • 1
  1. 1.Department of Bioscience at NOVUM Karolinska institutetHuddingeSweden

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