Geometry-based sampling of conformational transitions in proteins.

The fast and accurate prediction of protein flexibility is one of the major challenges in protein science. Enzyme activity, signal transduction, and ligand binding are dynamic processes involving essential conformational changes ranging from small side chain fluctuations to reorientations of entire domains. In the present work, we describe a reimplementation of the CONCOORD approach, termed tCONCOORD, which allows a computationally efficient sampling of conformational transitions of a protein based on geometrical considerations. Moreover, it allows for the extraction of the essential degrees of freedom, which, in general, are the biologically relevant ones. The method rests on a reliable estimate of the stability of interactions observed in a starting structure, in particular those interactions that change during a conformational transition. Applications to adenylate kinase, calmodulin, aldose reductase, T4-lysozyme, staphylococcal nuclease, and ubiquitin show that experimentally known conformational transitions are faithfully predicted.

[1]  Michael Nilges,et al.  The impact of protein flexibility on protein–protein docking , 2004, Proteins.

[2]  Ariel Fernández,et al.  Dynamics of hydrogen bond desolvation in protein folding. , 2002, Journal of molecular biology.

[3]  Ariel Fernández,et al.  Three-body correlations in protein folding: the origin of cooperativity , 2002 .

[4]  E Carafoli,et al.  NMR solution structure of a complex of calmodulin with a binding peptide of the Ca2+ pump. , 1999, Biochemistry.

[5]  Gert Vriend,et al.  The precision of NMR structure ensembles revisited , 2003, Journal of biomolecular NMR.

[6]  Heather A Carlson,et al.  Incorporating protein flexibility in structure-based drug discovery: using HIV-1 protease as a test case. , 2004, Journal of the American Chemical Society.

[7]  NMR solution structure of a complex of calmodulin with a binding peptide of the Ca2+ pump. , 1999 .

[8]  M. Brownlee.  Biochemistry and molecular cell biology of diabetic complications , 2001, Nature.

[9]  H. Carlson.  Protein flexibility and drug design: how to hit a moving target. , 2002, Current opinion in chemical biology.

[10]  David W Ritchie,et al.  Docking essential dynamics eigenstructures , 2005, Proteins.

[11]  S. Teague.  Implications of protein flexibility for drug discovery , 2003, Nature Reviews Drug Discovery.

[12]  W. Cook,et al.  Drug binding by calmodulin: crystal structure of a calmodulin-trifluoperazine complex. , 1994, Biochemistry.

[13]  F A Quiocho,et al.  Calmodulin structure refined at 1.7 A resolution. , 1992, Journal of molecular biology.

[14]  Berk Hess,et al.  GROMACS 3.0: a package for molecular simulation and trajectory analysis , 2001 .

[15]  H. Berendsen,et al.  Domain motions in bacteriophage T4 lysozyme: A comparison between molecular dynamics and crystallographic data , 1998, Proteins.

[16]  C. Sander,et al.  Positioning hydrogen atoms by optimizing hydrogen‐bond networks in protein structures , 1996, Proteins.

[17]  I. Kuntz,et al.  Molecular docking to ensembles of protein structures. , 1997, Journal of molecular biology.

[18]  D. Jacobs,et al.  Protein flexibility predictions using graph theory , 2001, Proteins.

[19]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[20]  G. Schulz,et al.  The structure of bovine mitochondrial adenylate kinase: Comparison with isoenzymes in other compartments , 1996, Protein science : a publication of the Protein Society.

[21]  Oliver F. Lange,et al.  Flooding in GROMACS: Accelerated barrier crossings in molecular dynamics , 2006, J. Comput. Chem..

[22]  P. Krüger,et al.  Targeted molecular dynamics: a new approach for searching pathways of conformational transitions. , 1994, Journal of molecular graphics.

[23]  G. Schulz,et al.  Structure of the complex between adenylate kinase from Escherichia coli and the inhibitor Ap5A refined at 1.9 A resolution. A model for a catalytic transition state. , 1992, Journal of molecular biology.

[24]  G. Klebe,et al.  Expect the unexpected or caveat for drug designers: multiple structure determinations using aldose reductase crystals treated under varying soaking and co-crystallisation conditions. , 2006, Journal of molecular biology.

[25]  G. Vriend,et al.  Prediction of protein conformational freedom from distance constraints , 1997, Proteins.

[26]  Y. Sugita,et al.  Replica-exchange molecular dynamics method for protein folding , 1999 .

[27]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[28]  A. Brünger,et al.  Conformational variability of solution nuclear magnetic resonance structures. , 1995, Journal of molecular biology.

[29]  Mark Gerstein,et al.  Normal mode analysis of macromolecular motions in a database framework: Developing mode concentration as a useful classifying statistic , 2002, Proteins.

[30]  G. Schulz,et al.  Adenylate kinase motions during catalysis: an energetic counterweight balancing substrate binding. , 1996, Structure.

[31]  M. Gerstein,et al.  A database of macromolecular motions. , 1998, Nucleic acids research.

[32]  W E Stites,et al.  Increasing the thermostability of staphylococcal nuclease: implications for the origin of protein thermostability. , 2000, Journal of molecular biology.

[33]  A. Atilgan,et al.  Vibrational Dynamics of Folded Proteins: Significance of Slow and Fast Motions in Relation to Function and Stability , 1998 .

[34]  Alexandre M J J Bonvin,et al.  Flexible protein-protein docking. , 2006, Current opinion in structural biology.

[35]  H. Berendsen,et al.  Essential dynamics of proteins , 1993, Proteins.

[36]  Martin Karplus,et al.  Simulation of conformational transitions by the restricted perturbation-targeted molecular dynamics method. , 2005, The Journal of chemical physics.

[37]  N. Go,et al.  Dynamics of a small globular protein in terms of low-frequency vibrational modes. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[39]  V. Dive,et al.  Accounting for Conformational Variability in NMR Structure of Cyclopeptides: Ensemble Averaging of Interproton Distance and Coupling Constant Restraints , 1997 .

[40]  G Vriend,et al.  WHAT IF: a molecular modeling and drug design program. , 1990, Journal of molecular graphics.

[41]  M. Karplus,et al.  Harmonic dynamics of proteins: normal modes and fluctuations in bovine pancreatic trypsin inhibitor. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Bert L de Groot,et al.  Atomic contacts in protein structures. A detailed analysis of atomic radii, packing, and overlaps , 2007, Proteins.

[43]  B. Shoichet,et al.  Information decay in molecular docking screens against holo, apo, and modeled conformations of enzymes. , 2003, Journal of medicinal chemistry.

[44]  Karsten Suhre,et al.  ElNémo: a normal mode web server for protein movement analysis and the generation of templates for molecular replacement , 2004, Nucleic Acids Res..

[45]  H. Scheraga,et al.  Inhibitor design by wrapping packing defects in HIV-1 proteins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Karsten Suhre,et al.  On the potential of normal-mode analysis for solving difficult molecular-replacement problems. , 2004, Acta crystallographica. Section D, Biological crystallography.

[47]  Ariel Fernández,et al.  Extent of hydrogen-bond protection in folded proteins: a constraint on packing architectures. , 2002, Biophysical journal.

[48]  G. Schulz,et al.  Structure of a mutant adenylate kinase ligated with an ATP-analogue showing domain closure over ATP. , 1996, Journal of molecular biology.

[49]  Grubmüller,et al.  Predicting slow structural transitions in macromolecular systems: Conformational flooding. , 1995, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[50]  Mark Gerstein,et al.  Normal modes for predicting protein motions: A comprehensive database assessment and associated Web tool , 2005, Protein science : a publication of the Protein Society.

[51]  I. Bahar,et al.  Gaussian Dynamics of Folded Proteins , 1997 .

[52]  Z. Zolnai,et al.  Solution structures of staphylococcal nuclease from multidimensional, multinuclear NMR: Nuclease-H124L and its ternary complex with Ca2+ and thymidine-3′,5′-bisphosphate , 1997, Journal of biomolecular NMR.