Computational Approaches to Modeling Receptor Flexibility Upon Ligand Binding: Application to Interfacially Activated Enzymes

  • R. C. Wade
  • V. Sobolev
  • A. R. Ortiz
  • G. Peters
Part of the NATO ASI Series book series (NSSE, volume 352)


Receptors generally undergo conformational change upon ligand binding. We describe how fairly simple techniques may be used in docking and design studies to account for some of the changes in the conformations of proteins on ligand binding. Simulations of protein-ligand interactions that give a more complete description of the dynamics important for ligand binding are then discussed. These methods are illustrated for phospholipase A2 and lipase, enzymes that both undergo interfacial activation.


Ligand Binding Quantitative Structure Activity Relationship Brownian Dynamic Interfacial Activation Miehei Lipase 
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.



Brownian dynamics


human synovial fluid phospholipase A2


molecular dynamics


nuclear magnetic resonance


quantitative structure activity relationship


root mean square deviation


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  1. 1.
    Ramirez, F. and Jain, M.K. (1991) Phospholipase A2 at the bilayer interface, Proteins, 9, 229–239.CrossRefGoogle Scholar
  2. 2.
    Pieroni, G., Gargouri, Y., Sarda, L. and Verger, R. (1990) Interactions of lipases with lipid monolayers. Facts and questions., Adv. Colloid Interface Sci., 32, 341–378.CrossRefGoogle Scholar
  3. 3.
    Sobolev, V., Wade, R.C., Vriend, G. and Edelman, M. (1996) Molecular Docking Using Surface Complementarity, 25, 120–129.Google Scholar
  4. 4.
    Scott, D.L., White, S.P., Browning, J.L., Rosa, J.J., Gelb, M.H. and Sigler, P.B. (1991) Structures of Free and Inhibited Human Secretory Phospolipase A2 from Inflamatory Exudate, Science, 254, 1007–1010.CrossRefGoogle Scholar
  5. 5.
    Pisabarro, M.T., Ortiz, A.R., Palomer, A., Cabre, F., Garcia, L., Wade, R.C., Gago, F., et al. (1994) Rational Modification of Human Synovial Fluid Phospholipase A2 Inhibitors, J. Med. Chem., 37, 337–341.CrossRefGoogle Scholar
  6. 6.
    Ortiz, A.R., Pisabarro, M.T., Gago, F. and Wade, R.C. (1995) Prediction of Drug Binding Affinities by comparative Binding Energy Analysis, J. Med. Chem., 38, 2681–2691.CrossRefGoogle Scholar
  7. 7.
    Ortiz, A.R., Pastor, M., Palomer, A., Cruciani, G., Gago, F. and Wade, R.C. (1996) Reliability of COMFA Models: Effects of Data Scaling and Variable Selection using a Set of Human Synovial Fluid Phospholipase A2 inhibitors, submitted,Google Scholar
  8. 8.
    Baroni, M., Constantino, G., Cruciani, G., Riganelli, D., Valigi, R. and Clementi, S. (1993) Generating Optimal Linear PLS Estimations (GOLPE): An advanced chemometric tool for handling 3D-QSAR problems, Quant. Struct. Act. Relat., 12, 9–20.CrossRefGoogle Scholar
  9. 9.
    van den Berg, B., Tessari, M., Boelens, R., Dijkman, R., de Haas, G.H., Kaptein, R. and Verheij, H. (1995) NMR structures of phospholipase A2 reveal conformational changes during interfacial activation, Nature Structure Biology, 2, 402–406.CrossRefGoogle Scholar
  10. 10.
    Holloway, M.K., Wai, J.M., Halgren, T.A., Fitzgerald, P.M.D., Vacca, J.P., Dorsey, B.D., Levin, R.B., et al. (1995) A priori predictions of activity for HIV-1 protease inhibitors employing energy minimization in the active site, J. Med. Chem., 38, 305–317.CrossRefGoogle Scholar
  11. 11.
    Grootenhuis, P.D.J. and van Galen, P.J.M. (1995) Correlation of Binding Affinities with Non-bonded Interaction Energies of Thrombin-Inhibitor Complexes, Acta Cryst. D., 51, 560–566.CrossRefGoogle Scholar
  12. 12.
    Sessions, R.B., Dauber-Osguthorpe, P. and Osguthorpe, D.J. (1988) Filtering Molecular Dynamics Trajectories to Reveal Low-frequency Collective Motions: Phospholipase A2, J. Mol. Biol., 209, 617–633.Google Scholar
  13. 13.
    Zhou, F. and Schulten, K. (1996) Molecular dynamics study of phospholipase A2 on a membrane surface, Proteins, 25, 12–27.CrossRefGoogle Scholar
  14. 14.
    Derewenda, U., Brzozowski, A.M., Lawson, D.M. and Derewenda, Z.S. (1992) Catalysis at the interface: the anatomy of a conformational change in a triglyceride lipase, Biochemistry, 31, 1532–1541.CrossRefGoogle Scholar
  15. 15.
    Brzozowski, A.M., Derewenda, U., Derewenda, Z.S., Dodson, G.G., Lawson, D.M., Turkenburg, J.P., Bjorkling, F., et al. (1991) A model for interfacial activation in lipases from the structure of a fungal lipase-inhibitor complex, Nature, 351, 491–494.CrossRefGoogle Scholar
  16. 16.
    Derewenda, Z.S., Derewenda, U. and Dodson, G.G. (1992) The crystal and molecular structure of the Rhizomucor miehei triacylglyceride lipase at 1.9 angstroms resolution, J. Mol. Biol., 227, 818–839.CrossRefGoogle Scholar
  17. 17.
    Norin, M., Olson, O.H., Svendsen, A., Edholm, O. and Hult, K. (1993) Theoretical studies of Rhizomucor miehei lipase activation, Protein Eng., 6, 855–863.CrossRefGoogle Scholar
  18. 18.
    Peters, G.H., Olsen, O.H., Svendsen, A. and Wade, R.C. (1996) Theoretical investigation of the dynamics of the Active Site Lid in Rhizomucor Miehei Lipase, Biophys. J., 71,Google Scholar
  19. 19.
    Levitt, M. (1976) A Simplified Representation of Protein, J. Mol. Biol., 104, 59–107.CrossRefGoogle Scholar
  20. 20.
    McCammon, J.A., Northrup, S.H., Karplus, M. and Levy, R.M. (1980) Helix-Coil Transitions in a Simple Polypeptide Model”, Biopolymers, 19, 2033–2045.CrossRefGoogle Scholar
  21. 21.
    Wade, R.C., Luty, B.A., Demchuk, E., Madura, J.D., Davis, M.E., Briggs, J.M. and McCammon, J.A. (1994) Simulation of enzyme-substrate encounter with gated active sites, Nature Struct. Biol, 1, 65–69.CrossRefGoogle Scholar
  22. 22.
    Holmquist, M., Norin, M. and Hult, K. (1993) The role of arginines in stabilizing the active ioen-lid conformation of Rhizomucor miehei lipase, Lipids, 28, 721–726.CrossRefGoogle Scholar
  23. 23.
    Norin, M., Haeffner, F., Hult, K. and Edholm, O. (1994) Molecular dynamics simulations of an enzyme surrounded by vacuum, water or a hydrophobic solvent, Biophys. J., 67, 548–559.CrossRefGoogle Scholar
  24. 24.
    Peters, G.H., van Aalten, D.M.F., Edholm, O., Toxvaerd, S. and Bywater, R. (1996) Dynamics of proteins in different solvent systems: Analysis of essential motion in lipases, submitted. Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • R. C. Wade
    • 1
  • V. Sobolev
    • 2
  • A. R. Ortiz
    • 1
  • G. Peters
    • 3
    • 4
  1. 1.European Molecular Biology LaboratoryHeidelbergGermany
  2. 2.Department of Plant GeneticsWeizmann Institute of ScienceRehovotIsrael
  3. 3.Chemistry DepartmentUniversity of CopenhagenCopenahagenDenmark
  4. 4.Novo NordiskBagsvaerdDenmark

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