Article thumbnail
Location of Repository

Refinement of docked protein–ligand and protein–DNA structures using low frequency normal mode amplitude optimization

By Erik Lindahl and Marc Delarue


Prediction of structural changes resulting from complex formation, both in ligands and receptors, is an important and unsolved problem in structural biology. In this work, we use all-atom normal modes calculated with the Elastic Network Model as a basis set to model structural flexibility during formation of macromolecular complexes and refine the non-bonded intermolecular energy between the two partners (protein–ligand or protein–DNA) along 5–10 of the lowest frequency normal mode directions. The method handles motions unrelated to the docking transparently by first applying the modes that improve non-bonded energy most and optionally restraining amplitudes; in addition, the method can correct small errors in the ligand position when the first six rigid-body modes are switched on. For a test set of six protein receptors that show an open-to-close transition when binding small ligands, our refinement scheme reduces the protein coordinate cRMS by 0.3–3.2 Å. For two test cases of DNA structures interacting with proteins, the program correctly refines the docked B-DNA starting form into the expected bent DNA, reducing the DNA cRMS from 8.4 to 4.8 Å and from 8.7 to 5.4 Å, respectively. A public web server implementation of the refinement method is available at

Topics: Article
Publisher: Oxford University Press
Year: 2005
DOI identifier: 10.1093/nar/gki730
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (1995). A limited memory algorithm for bound constrained optimization.
  2. (1994). A new approach for determining low-frequency normal modes in macromolecules.
  3. (2004). A normal mode analysis of structuralplasticityinthebiomolecularmotorF(1)-ATPase.J.Mol.Biol.,
  4. (2003). A protein–protein docking benchmark.
  5. (1993). A well-behaved electrostatic potential based method using charge Nucleic Acids Research,
  6. (1998). Analysis of domain motions by approximate normal mode calculations.
  7. and Gerstein,M.(2002)Normalmodeanalysisofmacromolecularmotionsin a database framework: developing mode concentration as a useful classifying statistic.
  8. (2001). Anisotropy of fluctuation dynamics of proteins with an elastic network model.
  9. (2003). Application of statistical potentials to protein structure refinement from low resolution ab initio models.
  10. (1998). ARPACK Users’ Guide: Solution of Large-Scale Eigenvalue Problems with Implicitly Restarted Arnoldi Methods.
  11. (2003). Assessment of blindpredictionsofprotein–proteininteractions:currentstatusofdocking methods.
  12. (2003). Assessment of homology-based predictions
  13. (2003). Assessment of progress over the CASP experiments.
  14. Atligan,A.R.and Erman,B.(1997) Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential.
  15. (2000). Building-block approach for determining low-frequency normal modes of macromolecules.
  16. (2003). CAPRI: a critical assessment of predicted interactions.
  17. (1983). CHARMM: a program for macromolecular energy, minimization, and dynamics calculation.
  18. (2002). Computational methods for the prediction of protein interactions.
  19. (2004). Conformational changes associated with protein–protein interactions.
  20. (2005). Conformational changes observed in enzyme crystal structures upon substrate binding.
  21. (1963). Correlation of structure and function in enzyme action.
  22. (1985). Crystallographic refinement of yeast tRNA-Asp.
  23. (1998). Databases in protein crystallography.
  24. Davies,J.M.,Tsuruta,H.,May,A.P.andWeis,W.I.(2005)Conformational changes of p97 during nucleotide hydrolysis determined by small-angle X-Ray scattering.
  25. (2005). Determining the structure of an unliganded and fully glycosylated SIV gp120 envelope glycoprotein.
  26. (2003). Dynamic reorganization of the functionally active ribosome explored by normal mode analysis and cryo-electronmicroscopy.
  27. (1983). Dynamics of a small globular proteinintermsoflow-frequencyvibrationalmodes.Proc.NatlAcad.Sci.
  28. (2001). Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides.
  29. (2001). FlexE: efficient molecular docking considering protein structure variations.
  30. (1992). Free R value: a novel statistical quantity for assessing the accuracy of crystal structures.
  31. (2005). Generation of native-like protein structures from limited NMR data, modern force fields and advanced conformational sampling.
  32. (1983). Harmonic dynamics of proteins: normal modes and fluctuations in bovine pancreatic trypsin inhibitor.
  33. (1999). Harmonic modes as variables to approximatelyaccountforreceptorflexibilityinligand-receptordocking simulations: application to DNA minor groove ligand complex.
  34. Hess,B.andvan der Spoel,D.(2001) Gromacs3.0: a package for molecular simulation and trajectory analysis.
  35. (1995). Hinge-bending motion in citrate synthase arising from normal mode calculations.
  36. (2004). Identification of specific interactions that drive ligand-induced closure in five enzymes with classic domain movements.
  37. (2003). Implications of protein flexibility for drug discovery.
  38. (2004). Improvement of comparative model accuracy by free-energyoptimization along principalcomponents of natural structural variation.
  39. (2004). Investigating the accessibility of the closed domainconformation of citrate synthase using essential dynamics sampling.
  40. Koehl,P.andDelarue,M.(1994)Polarandnonpolaratomicenvironments in the protein core: implications for folding and binding.
  41. (1996). Large amplitude elastic motions in proteins from a single-parameter, atomic analysis.
  42. (2003). Low-resolution structure refinement in electron microscopy.
  43. (1997). Model-free methods of analyzing domain motions in proteins from simulations: a comparison of normal mode analysis and molecular dynamics simulation.
  44. (2001). Molecular dynamics in the endgame of protein structure prediction.
  45. (2003). MolMovDB: analysis and visualization of conformational change and structural flexibility.
  46. Murphy,P., Schonbrun,J.,Strauss,C.E.M.andBaker,D.(2003)Rosettapredictionsin CASP5: successes, failures, and prospects for complete automation.
  47. (2004). Normal mode based flexible fitting of high-resolution structure into low-resolution experimental data from cryo-EM.
  48. (2005). Normal mode-based fitting of atomic structure into electron density maps: application to sarcoplasmic reticulum Ca-ATPase.
  49. (2004). On the potential of normal-mode analysis for solving difficult molecular-replacement problems.
  50. (2004). On the use of low-frequency normal modes to enforce collective movements in refining macromolecular structural models.
  51. (2002). Predictions of protein–protein interactions by docking methods.
  52. (2002). Principles of docking: an overview of search algorithms and a guide to scoring functions.
  53. (2004). ProDRG— a tool for high-throughput crystallography of protein–ligand complexes.
  54. (2004). Protein flexibility in ligand docking and virtual screening to protein kinases.
  55. (1983). Protein folding by restrained energy minimization and molecular dynamics.
  56. (1985). Protein normal-mode dynamics: trypsin inhibitor, crambin, ribonuclease and lysozyme.
  57. (2004). Protein structure prediction using Rosetta.
  58. (1982). Rapid comparison of protein structures.
  59. (2004). Refinement of homology-based protein structures by molecular dynamics simulation techniques.
  60. (2002). Simplified normal mode analysis of conformational transitions in DNA-dependent polymerases: the elastic network model.
  61. (1986). Solvation energy in protein folding and binding.
  62. Tama,F.andSanejouand,Y.-H.(2001)Conformationalchangeofproteins arising from normal mode calculations.
  63. (1997). The kinetics of protein–protein recognition.
  64. (2002). The mechanism and pathway of pH induced swelling in cowpea chlorotic mottle virus.
  65. (2003). Touchstone: a unified approach to protein structure prediction.
  66. Zacharias,M.(2004)Rapidprotein–liganddockingusingsoftmodesfrom Molecular Dynamics simulations to account for protein deformability: binding of FK505 to FKBP.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.